Targeted chromosomal genomic alterations with modified single stranded oligonucleotides

ABSTRACT

Presented are methods and compositions for targeted chromosomal genomic alterations using modified single-stranded oligonucleotides. The oligonucleotides of the invention have at least one modified nuclease-resistant terminal region comprising phosphorothioate linkages, LNA analogs or 2′-0-Me base analogs.

FIELD OF THE INVENTION

[0001] The technical field of the invention is oligonucleotide-directedrepair or alteration of genetic information using novel chemicallymodified oligonucleotides. Such genetic information is preferably from aeukaryotic organism, i.e. a plant, animal or fungus.

BACKGROUND OF THE INVENTION

[0002] A number of methods have been developed specifically to alter thesequence of an isolated DNA in addition to methods to alter directly thegenomic information of various plants, fungi and animals, includinghumans (“gene therapy”). The latter methods generally include the use ofviral or plasmid vectors carrying nucleic acid sequences encodingpartial or complete portions of a particular protein which is expressedin a cell or tissue to effect the alteration. The expression of theparticular protein then results in the desired phenotype. For example,retroviral vectors containing a transgenic DNA sequence allowing for theproduction of a normal CFTR protein when administered to defective cellsare described in U.S. Pat. No. 5,240,846. Others have developeddifferent “gene therapy vectors” which include, for example, portions ofadenovirus (Ad) or adeno-associated virus (AAV), or other viruses. Thevirus portions used are often long terminal repeat sequences which areadded to the ends of a transgene of choice along with other necessarycontrol sequences which allow expression of the transgene. See U.S. Pat.Nos. 5,700,470 and 5,139,941. Similar methods have been developed foruse in plants. See, for example, U.S. Pat. No. 4,459,355 which describesa method for transforming plants with a DNA vector and U.S. Pat. No.5,188,642 which describes cloning or expression vectors containing atransgenic DNA sequence which when expressed in plants confersresistance to the herbicide glyphosate. The use of such transgenevectors in any eukaryotic organism adds one or more exogenous copies ofa gene, which gene may be foreign to the host, in a usually randomfashion at one or more integration sites of the organism's genome atsome frequency. The gene which was originally present in the genome,which may be a normal allelic variant, mutated, defective, and/orfunctional, is retained in the genome of the host.

[0003] These methods of gene correction are problematic in thatcomplications which can compromise the health of the recipient, or evenlead to death, may result. One such problem is that insertion ofexogenous nucleic acid at random location(s) in the genome can havedeleterious effects. Another problem with such systems includes theaddition of unnecessary and unwanted genetic material to the genome ofthe recipient, including, for example, viral or other vector remnants,control sequences required to allow production of the transgene protein,and reporter genes or resistance markers. Such remnants and addedsequences may have presently unrecognized consequences, for example,involving genetic rearrangements of the recipient genomes. Otherproblems associated with these types of traditional gene therapy methodsinclude autoimmune suppression of cells expressing an inserted gene dueto the presence of foreign antigens. Concerns have also been raised withconsumption, especially by humans, of plants containing exogenousgenetic material.

[0004] More recently, simpler systems involving poly- oroligo-nucleotides have been described for use in the alteration ofgenomic DNA. These chimeric RNA-DNA oligonucleotides, requiringcontiguous RNA and DNA bases in a double-stranded molecule folded bycomplementarity into a double hairpin conformation, have been shown toeffect single basepair or frameshift alterations, for example, formutation or repair of plant or animal genomes. See, for example, WO99/07865 and U.S. Pat. No. 5,565,350. In the chimeric RNA-DNAoligonucleotide, an uninterrupted stretch of DNA bases within themolecule is required for sequence alteration of the targeted genomewhile the obligate RNA residues are involved in complex stability. Dueto the length, backbone composition, and structural configuration ofthese chimeric RNA-DNA molecules, they are expensive to synthesize anddifficult to purify. Moreover, if the RNA-containing strand of thechimeric RNA-DNA oligonucleotide is designed so as to direct geneconversion, a series of mutagenic reactions resulting in nonspecificbase alteration can result. Such a result compromises the utility ofsuch a molecule in methods designed to alter the genomes of plants andanimals, including in human gene therapy applications.

[0005] Alternatively, other oligo- or poly-nucleotides have been usedwhich require a triplex forming, usually polypurine or polypyrimidine,structural domain which binds to a DNA helical duplex through Hoogsteeninteractions between the major groove of the DNA duplex and theoligonucleotide. Such oligonucleotides may have an additional DNAreactive moiety, such as psoralen, covalently linked to theoligonucleotide. These reactive moieties function as effectiveintercalation agents, stabilize the formation of a triplex and can bemutagenic. Such agents may be required in order to stabilize the triplexforming domain of the oligonucleotide with the DNA double helix if theHoogsteen interactions from the oligonucleotide/target base compositionare insufficient See, e.g., U.S. Pat. No. 5,422,251. The utility ofthese oligonucleotides for directing gene conversion is compromised by ahigh frequency of nonspecific base changes.

[0006] In more recent work, the domain for altering a genome is linkedor tethered to the triplex forming domain of the bi-functionaloligonucleotide, adding an additional linking or tethering functionaldomain to the oligonucleotide. See, e.g., Culver et al., NatureBiotechnology 17: 989-93 (1999). Such chimeric or triplex formingmolecules have distinct structural requirements for each of thedifferent domains of the complete poly- or oligo-nucleotide in order toeffect the desired genomic alteration in either episomal or chromosomaltargets.

[0007] Other genes, e.g. CFTR, have been targeted by homologousrecombination using duplex fragments having several hundred basepairs.See, e.g., Kunzelmann et al., Gene Ther. 3:859-867 (1996). Earlyexperiments to mutagenize an antibiotic resistance indicator gene byhomologous recombination used an unmodified DNA oligonucleotide with nofunctional domains other than a region of complementary sequence to thetarget See Campbell et al., New Biologist 1: 223-227 (1989). Theseexperiments required large concentrations of the oligonucleotide,exhibited a very low frequency of episomal modification of a targetedexogenous plasmid gene not normally found in the cell and have not beenreproduced. However, as shown in the examples herein, we have observedthat an unmodified DNA oligonucleotide can convert a base at lowfrequency which is detectable using the assay systems described herein.

[0008] Artificial chromosomes can be useful for the screening purposedidentified herein. These molecules are man-made linear or circular DNAmolecules constructed from essential cis-acting DNA sequence elementsthat are responsible for the proper replication and partitioning ofnatural chromosomes (Murray et al., 1983). The essential elements are:(1) Autonomous Replication Sequences (ARS), (2) Centromeres, and (3)Telomeres.

[0009] Yeast artificial chromosomes (YACs) allow large genomic DNA to bemodified and used for generating transgenic animals [Burke et al.,Science 236:806; Peterson et al., Trends Genet. 13:61 (1997); Choi, etal., Nat. Genet, 4:117-223 (1993), Davies, et al., Biotechnology11:911-914(1993), Matsuura, et al., Hum. Mol. Genet, 5:451-459 (1996),Peterson et al., Proc. Natl. Acad. Sci., 93:6605-6609 (1996); andSchedl, et al., Cell, 86:71-82 (1996)]. Other vectors also have beendeveloped for the cloning of large segments of mammalian DNA, includingcosmids, and bacteriophage P1 [Sternberg et al., Proc. Natl. Acad. Sci.U.S.A, 87:103-107 (1990)]. YACs have certain advantages over thesealternative large capacity cloning vectors [Burke et al., Science,236:806-812 (1987)]. The maximum insert size is 35-30 kb for cosmids,and 100 kb for bacteriophage P1, both of which are much smaller than themaximal insert for a YAC.

[0010] An alternative to YACs are E. coli based cloning systems based onthe E. coli fertility factor that have been developed to construct largegenomic DNA insert libraries. They are bacterial artificial chromosomes(BACs) and P-1 derived artificial chromosomes (PACs) [Mejia et al.,Genome Res. 7:179-186 (1997); Shizuya et al., Proc. Natl. Acad. Sci.89:8794-8797 (1992); Ioannou et al., Nat. Genet, 6:84-89 (1994); Hosodaet al., Nucleic Acids Res. 18:3863 (1990)]. BACs are based on the E.coli fertility plasmid (F factor); and PACs are based on thebacteriophage P1. These vectors propagate at a very low copy number (1-2per cell) enabling genomic inserts up to 300 kb in size to be stablymaintained in recombination deficient hosts. Furthermore,.the PACs andBACs are circular DNA molecules that are readily isolated from the hostgenomic background by classical alkaline lysis [Birnboim et al., NucleicAcids Res. 7:1513-1523 (1979)].

[0011] Oligonucleotides designed for use in the alteration of geneticinformation are significantly different from oligonucleotides designedfor antisense approaches. For example, antisense oligonucleotides areperfectly complementary to and bind an mRNA strand in order to modifyexpression of a targeted mRNA and are used at high concentration. As aconsequence, they are unable to produce a gene conversion event byeither mutagenesis or repair of a defect in the chromosomal DNA of ahost genome. Furthermore, the backbone chemical composition used in mostoligonucleotides designed for use in antisense approaches renders theminactive as substrates for homologous pairing or mismatch repair enzymesand the high concentrations of oligonucleotide required for antisenseapplications can be toxic with some types of nucleotide modifications.In addition, antisense oligonucleotides must be complementary to themRNA and therefore, may not be complementary to the other DNA strand orto genomic sequences that span the junction between intron sequence andexon sequence.

[0012] A need exists for simple, inexpensive oligonucleotides capable ofproducing targeted alteration of genetic material such as thosedescribed herein as well as methods to identify optimal oligonucleotidesthat accurately and efficiently alter target DNA.

SUMMARY OF THE INVENTION

[0013] Novel, modified single-stranded nucleic acid molecules thatdirect gene alteration in plants, fungi and animals are identified andthe efficiency of alteration is analyzed both in vitro using a cell-freeextract assay and in vivo using a yeast cell system. The alteration inan oligonucleotide of the invention may comprise an insertion, deletion,substitution, as well as any combination of these. Site specificalteration of DNA is not only useful for studying function of proteinsin vivo, but it is also useful for creating animal models for humandisease, and in gene therapy. As described herein, oligonucleotides ofthe invention target directed specific gene alterations in genomicdouble-stranded DNA cells. The target DNA can be normal, cellularchromosomal DNA, extrachromosomal DNA present in cells in differentforms including, e.g., mammalian artificial chromosomes (MACs), PACsfrom P-1 vectors, yeast artificial chromosomes (YACs), bacterialartificial chromosomes (BACs), plant artificial chromosomes (PLACs), aswell as episomal DNA, including episomal DNA from an exogenous sourcesuch as a plasmid or recombinant vector. Many of these artificialchromosome constructs containing human DNA can be obtained from avariety of sources, including, e.g., the Whitehead Institute, and aredescribed, e.g., in Cohen et al., Nature 336:698-701 (1993) andChumakov, et al., Nature 377:174-297 (1995). The target DNA may betranscriptionally silent or active. In a preferred embodiment, thetarget DNA to be altered is the non-transcribed strand of a genomic DNAduplex.

[0014] The low efficiency of gene alteration obtained using unmodifiedDNA oligonucleotides is believed to be largely the result of degradationby nucleases present in the reaction mixture or the target cell.Although different modifications are known to have different effects onthe nuclease resistance of oligonucleotides or stability of duplexesformed by such oligonucleotides (see, e.g., Koshkin et al., J. Am. Chem.Soc., 120:13252-3), we have found that it is not possible to predictwhich of any particular known modification would be most useful for anygiven alteration event, including for the construction of geneconversion oligonucleotides, because of the interaction of different asyet unidentified proteins during the gene alteration event. Herein, avariety of nucleic acid analogs have been developed that increase thenuclease resistance of oligonucleotides that contain them, including,e.g., nucleotides containing phosphorothioate linkages or 2′-O-methylanalogs. We recently discovered that single-stranded DNAoligonucleotides modified to contain 2′-O-methyl RNA nucleotides orphosphorothioate linkages can enable specific alteration of geneticinformation at a higher level than either unmodified single-stranded DNAor a chimeric RNA/DNA molecule. See priority applications incorporatedherein in their entirety; see also Gamper et al., Nucleic Acids Research28: 4332-4339 (2000). We also found that additional nucleic acid analogswhich increase the nuclease resistance of oligonucleotides that containthem, including, e.g., “locked nucleic acids” or “LNAs”, xylo-LNAs andL-ribo-LNAs; see, for example, Wengel & Nielsen, WO 99/14226; Wengel, WO00/56748 and Wengel, WO 00166604; also allow specific targetedalteration of genetic information.

[0015] The assay allows for determining the optimum length of theoligonucleotide, optimum sequence of the oligonucleotide, optimumposition of the mismatched base or bases, optimum chemical modificationor modifications, optimum strand targeted for identifying and selectingthe most efficient oligonucleotide for a particular gene alterationevent by comparing to a control oligonucleotide. Controloligonucleotides may include a chimeric RNA-DNA double hairpinoligonucleotide directing the same gene alteration event, anoligonucleotide that matches its target completely, an oligonucleotidein which all linkages are phosphorothiolated, an oligonucleotide fullysubstituted with 2′-O-methyl analogs or an RNA oligonucleotide. Suchcontrol oligonucleotides either fail to direct a targeted alteration ordo so at a lower efficiency as compared to the oligonucleotides of theinvention. The assay further allows for determining the optimum positionof a gene alteration event within an oligonucleotide, optimumconcentration of the selected oligonucleotide for maximum alterationefficiency by systematically testing a range of concentrations, as wellas optimization of either the source of cell extract by testingdifferent organisms or strains, or testing cells derived from differentorganisms or strains, or cell lines. Using a series of single-strandedoligonucleotides, comprising all RNA or DNA residues and variousmixtures of the two, several new structures are identified as viablemolecules in nucleotide conversion to direct or repair a genomicmutagenic event When extracts from mammalian, plant and fungal cells areused and are analyzed using a genetic readout assay in bacteria,single-stranded oligonucleotides having one of several modifications arefound to be more active than a control RNA-DNA double hairpin chimerastructure when evaluated using an in vitro gene repair assay. Similarresults are also observed in vivo using yeast, mammalian, rodent,monkey, human and embryonic cells, including stem cells. Moleculescontaining various lengths of modified bases were found to possessgreater activity than unmodified single-stranded DNA molecules.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention provides oligonucleotides having chemicallymodified, nuclease resistant residues, preferably at or near the terminiof the oligonucleotides, and methods for their identification and use intargeted alteration of genetic material, including gene mutation,targeted gene repair and gene knockout. The oligonucleotides arepreferably used for mismatch repair or alteration by changing at leastone nucleic acid base, or for frameshift repair or alteration byaddition or deletion of at least one nucleic acid base. Theoligonucleotides of the invention direct any such alteration, includinggene correction, gene repair or gene mutation and can be used, forexample, to introduce a polymorphism or haplotype or to eliminate(“knockout”) a particular protein activity.

[0017] The oligonucleotides of the invention are designed as substratesfor homologous pairing and repair enzymes and as such have a uniquebackbone composition that differs from chimeric RNA-DNA double hairpinoligonucleotides, antisense oligonucleotides, and/or other poly- oroligo-nucleotides used for altering genomic DNA, such as triplex formingoligonucleotides. The single-stranded oligo-nucleotides described hereinare inexpensive to synthesize and easy to purify. In side-by-sidecomparisons, an optimized single-stranded oligonucleotide comprisingmodified residues as described herein is significantly more efficientthan a chimeric RNA-DNA double hairpin oligonucleotide in directing abase substitution or frameshift mutation in a cell-free extract assay.

[0018] We have discovered that single-stranded oligonucleotides having aDNA domain surrounding the targeted base, with the domain preferablycentral to the poly- or oligo-nucleotide, and having at least onemodified end, preferably at the 3′ terminal region are able to alter atarget genetic sequence and with an efficiency that is higher thanchimeric RNA-DNA double hairpin oligonucleotides disclosed in U.S. Pat.No. 5,565,350. Oligonucleotides of the invention can efficiently be usedto introduce targeted alterations in a genetic sequence of DNA in thepresence of human, animal, plant, fungal (including yeast) proteins andin cultured cells of human liver, lung, colon, cervix, kidney,epethelium and cancer cells and in monkey, hamster, rat and mouse cellsof different types, as well as embryonic stem cells. Cells for use inthe invention include, e.g., fungi including S. cerevisiae, Ustillagomaydis and Candida albicans, mammalian, mouse, hamster, rat, monkey,human and embryonic cells including stem cells. The DNA domain ispreferably fully complementary to one strand of the gene target, exceptfor the mismatch base or bases responsible for the gene alteration orconversion events. On either side of the preferably central DNA domain,the contiguous bases may be either RNA bases or, preferably, areprimarily DNA bases. The central DNA domain is generally at least 8nucleotides in length. The base(s) targeted for alteration in the mostpreferred embodiments are at least about 8, 9 or 10 bases from one endof the oligonucleotide.

[0019] According to certain embodiments, the termini of theoligonucleotides of the present invention comprise phosphorothioatemodifications, LNA backbone modifications, or 2′-O-methyl base analogs,or any combination of these modifications. Oligonucleotides comprising2′-O-methyl or LNA analogs are a mixed DNA/RNA polymer. Theseoligonucleotides are, however, single-stranded and are not designed toform a stable internal duplex structure within the oligonucleotide. Theefficiency of gene alteration is surprisingly increased witholigonucleotides having internal complementary sequence comprisingphosphorothioate modified bases as compared to 2′-O-methylmodifications. This result indicates that specific chemical interactionsare involved between the converting oligonucleotide and the proteinsinvolved in the conversion. The effect of other such chemicalinteractions to produce nuclease resistant termini using modificationsother than LNA, phosphorothioate linkages, or 2′-O-methyl analogincorporation into an oligonucleotide can not yet be predicted becausethe proteins involved in the alteration process and their particularchemical interaction with the oligonucleotide substituents are not yetknown and cannot be predicted.

[0020] In the examples, correcting oligonucleotides of defined sequenceare provided for correction of genes mutated in human diseases. In thetables of these examples, the oligonucleotides of the invention are notlimited to the particular sequences disclosed. The oligonucleotides ofthe invention include extensions of the appropriate sequence of thelonger 120 base oligonucleotides which can be added base by base to thesmallest disclosed oligonucleotides of 17 bases. Thus theoligonucleotides of the invention include for each correcting change,oligonucleotides of length 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,115, 116, 117, 118, 119, or 120 with further single-nucleotide additionsup to the longest sequence disclosed. Moreover, the oligonucleotides ofthe invention do not require a symmetrical extension on either side ofthe central DNA domain. Similarly, the oligonucleotides of the inventionas disclosed in the various tables for correction of human diseasescontain phosphorothioate linkages, 2′-O-methyl analogs or LNAs or anycombination of these modifications just as the assay oligonucleotidesdo.

[0021] The present invention, however, is not limited tooligonucleotides that contain any particular nuclease resistantmodification. Oligonucleotides of the invention may be altered with anycombination of additional LNAs, phosphorothioate linkages or 2′-O-methylanalogs to maximize conversion efficiency. For oligonucleotides of theinvention that are longer than about 17 to about 25 bases in length,internal as well as terminal region segments of the backbone may bealtered. Alternatively, simple fold-back structures at each end of aoligonucleotide or appended end groups may be used in addition to amodified backbone for conferring additional nuclease resistance.

[0022] The different oligonucleotides of the present inventionpreferably contain more than one of the aforementioned backbonemodifications at each end. In some embodiments, the backbonemodifications are adjacent to one another. However, the optimal numberand placement of backbone modifications for any individualoligonucleotide will vary with the length of the oligonucleotide and theparticular type of backbone modification(s) that are used. If constructsof identical sequence having phosphorothioate linkages are compared, 2,3, 4, 5, or 6 phosphorothioate linkages at each end are preferred. Ifconstructs of identical sequence having 2′-O-methyl base analogs arecompared, 1, 2, 3 or 4 analogs are preferred. The optimal number andtype of backbone modifications for any particular oligo-nucleotideuseful for altering target DNA may be determined empirically bycomparing the alteration efficiency of the oligonucleotide comprisingany combination of the modifications to a control molecule of comparablesequence using any of the assays described herein. The optimalposition(s) for oligonucleotide modifications for a maximally efficientaltering oligonucleotide can be determined by testing the variousmodifications as compared to control molecule of comparable sequence inone of the assays disclosed herein. In such assays, a control moleculeincludes, e.g., a completely 2′-O-methyl substituted molecule, acompletely complementary oligonucleotide, or a chimeric RNA-DNA doublehairpin.

[0023] Increasing the number of phosphorothioate linkages, LNAs or2′-O-methyl bases beyond the preferred number generally decreases thegene repair activity of a 25 nucleotide long oligonucleotide. Based onanalysis of the concentration of oligonucleotide present in the extractafter different time periods of incubation, it is believed that theterminal modifications impart nuclease resistance to the oligonucleotidethereby allowing it to survive within the cellular environment However,this may not be the only possible mechanism by which such modificationsconfer greater efficiency of conversion. For example, as disclosedherein, certain modifications to oligonucleotides confer a greaterimprovement to the efficiency of conversion than other modifications.

[0024] Efficiency of conversion is defined herein as the percentage ofrecovered substate molecules that have undergone a conversion event.Depending on the nature of the target genetic material, e.g. the genomeof a cell, efficiency could be represented as the proportion of cells orclones containing an extrachromosomal element that exhibit a particularphenotype. Alternatively, representative samples of the target geneticmaterial can be sequenced to determine the percentage that have acquiredthe desire change. The oligonucleotides of the invention in differentembodiments can alter DNA one, two, three, four, five, six, seven,eight, nine, ten, twelve, fifteen, twenty, thirty, and fifty or morefold more than control oligonucleotides. Such control oligonucleotidesare oligonucleotides with fully phosphorothiolated linkages,oligonucleotides that are fully substituted with 2′-O-methyl analogs, aperfectly matched oligonucleotide that is fully complementary to atarget sequence or a chimeric DNA-RNA double hairpin oligonucleotidesuch as disclosed in U.S. Pat. No. 5,565,350.

[0025] In addition, for a given oligonucleotide length, additionalmodifications interfere with the ability of the oligonucleotide to actin concert with the cellular recombination or repair enzyme machinerywhich is necessary and required to mediate a targeted substitution,addition or deletion event in DNA. For example, fully phosphorothiolatedor fully 2-O-methylated molecules are inefficient in targeted genealteration.

[0026] The oligonucleotides of the invention as optimized for thepurpose of targeted alteration of genetic material, including geneknockout or repair, are different in structure from antisenseoligo-nucleotides that may possess a similar mixed chemical compositionbackbone. The oligonucleotides of the invention differ from suchantisense oligonucleotides in chemical composition, structure, sequence,and in their ability to alter genomic DNA. Significantly, antisenseoligonucleotides fail to direct targeted gene alteration. Theoligonucleotides of the invention may target either the Watson or theCrick strand of DNA and can include any component of the genomeincluding, for example, intron and exon sequences. The preferredembodiment of the invention is a modified oligonucleotide that binds tothe non-transcribed strand of a genomic DNA duplex. In other words, thepreferred oligonucleotides of the invention target the sense strand ofthe DNA, i.e. the oligonucleotides of the invention are complementary tothe non-transcribed strand of the target duplex DNA. The sequence of thenon-transcribed strand of a DNA duplex is found in the mRNA producedfrom that duplex, given that mRNA uses uracil-containing nucleotides inplace of thymine-containing nucleotides.

[0027] Moreover, the initial observation that single-strandedoligonucleotides comprising these modifications and lacking anyparticular triplex forming domain have reproducibly enhanced gene repairactivity in a variety of assay systems as compared to a chimeric RNA-DNAdouble-stranded hairpin control or single-stranded oligonucleotidescomprising other backbone modifications was surprising. Thesingle-stranded molecules of the invention totally lack thecomplementary RNA binding structure that stabilizes a normal chimericdouble-stranded hairpin of the type disclosed in U.S. Pat. No. 5,565,350yet is more effective in producing targeted base conversion as comparedto such a chimeric RNA-DNA double-stranded hairpin. In addition, themolecules of the invention lack any particular triplex forming domaininvolved in Hoogsteen interactions with the DNA double helix andrequired by other known oligonucleotides in other oligonucleotidedependant gene conversion systems. Although the lack of these functionaldomains was expected to decrease the efficiency of an alteration in asequence, just the opposite occurs: the efficiency of sequencealteration using the modified oligonucleotides of the invention ishigher than the efficiency of sequence alteration using a chimericRNA-DNA hairpin targeting the same sequence alteration. Moreover, theefficiency of sequence alteration or gene conversion directed by anmodified oligonucleotide is many times lower as compared to a controlchimeric RNA-DNA molecule or the modified oligonucleotides of theinvention targeting the same sequence alteration. Similarly, moleculescontaining at least 3 2′-O-methyl base analogs are about four to fivefold less efficient as compared to an oligonucleotide having the samenumber of phosphorothioate linkages, The oligonucleotides of the presentinvention for alteration of a single base are about 17 to about 121nucleotides in length, preferably about 17 to about 74 nucleotides inlength. Most preferably, however, the oligonucleotides of the presentinvention are at least about 25 bases in length, unless there areself-dimerization structures within the oligonucleotide. If theoligonucleotide has such an unfavorable structure, lengths longer than35 bases are preferred. Oligonucleotides with modified ends both shorterand longer than certain of the exemplified, modified oligonucleotidesherein function as gene repair or gene knockout agents and are withinthe scope of the present invention.

[0028] Once an oligomer is chosen, it can be tested for its tendency toself-dimerize, since self-dimerization may result in reduced efficiencyof alteration of genetic information. Checking for self-dimerizationtendency can be accomplished manually or, more preferably, by using asoftware program. One such program is Oligo Analyzer 2.0, availablethrough Integrated DNA Technologies (Coralville, Iowa 52241)(http://www.idtdna.com); this program is available for use on the worldwide web at

[0029] http://www.idtdna.com/program/oligoanalyzer/oligoanalyzer.asp.

[0030] For each oligonucleotide sequence input into the program, OligoAnalyzer 2.0 reports possible self-dimerized duplex forms, which areusually only partially duplexed, along with the free energy changeassociated with such self-dimerization. Delta G-values that are negativeand large in magnitude, indicating strong self-dimerization potential,are automatically flagged by the software as “bad”. Another softwareprogram that analyzes oligomers for pair dimer formation is PrimerSelect from DNASTAR, Inc., 1228 S. Park St., Madison, Wis. 53715, Phone:(608) 258-7420 (http://www.dnastar.com/products/PrimerSelect.html). Ifthe sequence is subject to significant self-dimerization, the additionof further sequence flanking the “repair” nucleotide can improve genecorrection frequency.

[0031] Generally, the oligonucleotides of the present invention areidentical in sequence to one strand of the target DNA, which can beeither strand of the target DNA, with the exception of one or moretargeted bases positioned within the DNA domain of the oligonucleotide,and preferably toward the middle between the modified terminal regions.Preferably, the difference in sequence of the oligonucleotide ascompared to the targeted genomic DNA is located at about the middle ofthe oligonucleotide sequence. In a preferred embodiment, theoligonucleotides of the invention are complementary to thenon-transcribed strand of a duplex. In other words, the preferredoligonucleotides target the sense strand of the DNA, i.e. theoligonucleotides of the invention are preferably complementary to thestrand of the target DNA the sequence of which is found in the mRNA.

[0032] The oligonucleotides of the invention can include more than asingle base change. In an oligonucleotide that is about a 70-mer, withat least one modified residue incorporated on the ends, as disclosedherein, multiple bases can be simultaneously targeted for change. Thetarget bases may be up to 27 nucleotides apart and may not be changedtogether in all resultant plasmids in all cases. There is a frequencydistribution such that the closer the target bases are to each other inthe central DNA domain within the oligonucleotides of the invention, thehigher the frequency of change in a given cell. Target bases only twonucleotides apart are changed together in every case that has beenanalyzed. The farther apart the two target bases are, the less frequentthe simultaneous change. Thus, oligonucleotides of the invention may beused to repair or alter multiple bases rather than just one single base.For example, in a 74-mer oligonucleotide having a central base targetedfor change, a base change event up to about 27 nucleotides away can alsobe effected. The positions of the altering bases within theoligonucleotide can be optimized using any one of the assays describedherein. Preferably, the altering bases are at least about 8 nucleotidesfrom one end of the oligonucleotide.

[0033] The oligonucleotides of the present invention can be introducedinto cells by any suitable means. According to certain preferredembodiments, the modified oligonucleotides may be used alone. Suitablemeans, however, include the use of polycations, cationic lipids,liposomes, polyethylenimine (PEI), electroporation, biolistics,microinjecton and other methods known in the art to facilitate cellularuptake. According to certain preferred embodiments of the presentinvention, the isolated cells are treated in culture according to themethods of the invention, to mutate or repair a target gene. Modifiedcells may then be reintroduced into the organism as, for example, inbone marrow having a targeted gene. Alternatively, modified cells may beused to regenerate the whole organism as, for example, in a plant havinga desired targeted genomic change. In other instances, targeted genomicalteration, including repair or mutagenesis, may take place in vivofollowing direct administration of the modified, single-strandedoligonucleotides of the invention to a subject.

[0034] The single-stranded, modified oligonucleotides of the presentinvention have numerous applications as gene repair, gene modification,or gene knockout agents. Such oligonucleotides may be advantageouslyused, for example, to introduce or correct multiple point mutations.Each mutation leads to the addition, deletion or substitution of atleast one base pair. The methods of the present invention offer distinctadvantages over other methods of altering the genetic makeup of anorganism, in that only the individually targeted bases are altered. Noadditional foreign DNA sequences are added to the genetic complement ofthe organism. Such agents may, for example, be used to develop plants oranimals with improved traits by rationally changing the sequence ofselected genes in cultured cells. Modified cells are then cloned intowhole plants or animals having the altered gene. See, e.g., U.S. Pat.No. 6,046,380 and U.S. Pat. No. 5,905,185 incorporated herein byreference. Such plants or animals produced using the compositions of theinvention lack additional undesirable selectable markers or otherforeign DNA sequences. Targeted base pair substitution or frameshiftmutations introduced by an oligo-nucleotide in the presence of acell-free extract also provides a way to modify the sequence ofextrachromosomal elements, including, for example, plasmids, cosmids andartificial chromosomes. The oligonucleotides of the invention alsosimplify the production of transgenic animals having particular modifiedor inactivated genes. Altered animal or plant model systems such asthose produced using the methods and oligonucleotides of the inventionare invaluable in determining the function of a gene and in evaluatingdrugs. The oligonucleotides and methods of the present invention mayalso be used for gene therapy to correct mutations causative of humandiseases.

[0035] The purified oligonucleotide compositions may be formulated inaccordance with routine procedures as a pharmaceutical compositionadapted for bathing cells in culture, for microinjection into cells inculture, and for intravenous administration to human beings or animals.Typically, compositions for cellular administration or for intravenousadministration into animals, including humans, are solutions in sterileisotonic aqueous buffer. Where necessary, the composition may alsoinclude a solubilizing agent and a local anaesthetic such as lignocaineto ease pain at the site of the injection. Generally, the ingredientswill be supplied either separately or mixed together in unit dosageform, for example, as a dry, lyophilized powder or water-freeconcentrate. The composition may be stored in a hermetically sealedcontainer such as an ampule or sachette indicating the quantity ofactive agent in activity units. Where the composition is administered byinfusion, it can be dispensed with an infusion bottle containing sterilepharmaceutical grade “water for injection” or saline. Where thecomposition is to be administered by injection, an ampule of sterilewater for injection or saline may be provided so that the ingredientsmay be mixed prior to administration.

[0036] Pharmaceutical compositions of this invention comprise thecompounds of the present invention and pharmaceutically acceptable saltsthereof, with any pharmaceutically acceptable ingredient, excipient,carrier, adjuvant or vehicle.

[0037] The oligonucleotides of the invention are preferably administeredto the subject in the form of an injectable composition. The compositionis preferably administered parenterally, meaning intravenously,intraarterially, intrathecally, interstitially or intracavitarilly.Pharmaceutical compositions of this invention can be administered tomammals including humans in a manner similar to other diagnostic ortherapeutic agents. The dosage to be administered, and the mode ofadministration will depend on a variety of factors including age,weight, sex, condition of the subject and genetic factors, and willultimately be decided by medical personnel subsequent to experimentaldeterminations of varying dosage as described herein. In general, dosagerequired for correction and therapeutic efficacy will range from about0.001 to 50,000 μg/kg, preferably between 1 to 250 μg/kg of host cell orbody mass, and most preferably at a concentration of between 30 and 60micromolar.

[0038] For cell administration, direct injection into the nucleus,biolistic bombardment, electroporation, liposome transfer and calciumphosphate precipitation may be used. In yeast, lithium acetate orspheroplast transformation may also be used. In a preferred method, theadministration is performed with a liposomal transfer compound, e.g.,DOTAP (Boehringer-Mannheim) or an equivalent such as lipofectin. Theamount of the oligonucleotide used is about 500 nanograms in 3micrograms of DOTAP per 100,000 cells. For electroporation, between 20and 2000 nanograms of oligonucleotide per million cells to beelectroporated is an appropriate range of dosages which can be increasedto improve efficiency of genetic alteration upon review of theappropriate sequence according to the methods described herein.

[0039] Another aspect of the invention is a kit comprising at least oneoligonucleotide of the invention. The kit may comprise an additionreagent or article of manufacture. The additional reagent or article ofmanufacture may comprise a cell extract, a cell, or a plasmid, such asone of those disclosed in the Figures herein, for use in an assay of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040]FIG. 1. Flow diagram for the generation of modifiedsingle-stranded oligonucleotides. The upper strands of chimericoligonucleotides I and II are separated into pathways resulting in thegeneration of single-stranded oligonucleotides that contain (A)2′-O-methyl RNA nucleotides or (B) phosphorothioate linkages. Foldchanges in repair activity for correction of kan^(s) in the HUH7cell-free extract are presented in parenthesis. HUH7 cells are describedin Nakabayashi et al., Cancer Research 42: 3858-3863 (1982). Eachsingle-stranded oligonucleotide is 25 bases in length and contains a Gresidue mismatched to the complementary sequence of the kan^(s) gene.The numbers 3, 6, 8, 10, 12 and 12.5 respectively indicate how manyphosphorothioate linkages (S) or 2′-O-methyl RNA nucleotides (R) are ateach end of the molecule. Hence oligo 12S/25G contains an allphosphorothioate backbone, displayed as a dotted line. Smooth linesindicate DNA residues, wavy lines indicate 2′-O-methyl RNA residues andthe carat indicates the mismatched base site (G). FIG. 1(C) provides aschematic plasmid indicating the sequence of the kan chimericdouble-stranded hairpin oligonucleotide (left) and the sequence the tetchimeric double-stranded hairpin oligonucleotide used in otherexperiments. FIG. 1(D) provides a flow chart of a kan experiment inwhich a chimeric double-stranded hairpin oligonucleotide is used.

[0041]FIG. 2. Genetic readout system for correction of a point mutationin plasmid pK^(s)m4021. A mutant kanamycin gene harbored in plasmidpK^(s)m4021 is the target for correction by oligonucleotides. The mutantG is converted to a C by the action of the oligo. Corrected plasmidsconfer resistance to kanamycin in E. coli (DH10B) after electroporationleading to the genetic readout and colony counts.

[0042]FIG. 3. Target plasmid and sequence correction of a frameshiftmutation by chimeric and single-stranded oligonucleotides. (A) PlasmidpT^(s)Δ208 contains a single base deletion mutation at position 208rendering it unable to confer tet resistance. The target sequencepresented below indicates the insertion of a T directed by theoligonucleotides to re-establish the resistant phenotype. (B) DNAsequence confirming base insertion directed by Tet 3S/25G; the yellowhighlight indicates the position of frameshift repair.

[0043]FIG. 4. DNA sequences of representative kan^(r) colonies.Confirmation of sequence alteration directed by the indicated moleculeis presented along with a table outlining codon distribution. Note that10S/25G and 12S/25G elicit both mixed and unfaithful gene repair. Thenumber of clones sequenced is listed in parentheses next to thedesignation for the single-stranded oligonucleotide. A plus (+) symbolindicates the codon identified while a figure after the (+) symbolindicates the number of colonies with a particular sequence. TAC/TAGindicates a mixed peak. Representative DNA sequences are presented belowthe table with yellow highlighting altered residues.

[0044]FIG. 5. Gene correction in HeLa cells. Representativeoligonucleotides of the invention are co-transfected with thepCMVneo(⁻)FIAsH plasmid (shown in FIG. 9) into HeLa cells. Ligand isdiffused into cells after co-transfection of plasmid andoligonucleotides. Green fluorescence indicates gene correction of themutation in the antibiotic resistance gene. Correction of the mutationresults in the expression of a fusion protein that carries a markerligand binding site and when the fusion protein binds the ligand, agreen fluorescence is emitted. The ligand is produced by AuroraBiosciences and can readily diffuse into cells enabling a measurement ofcorrected protein function; the protein must bind the ligand directly toinduce fluorescence. Hence cells bearing the corrected plasmid geneappear green while “uncorrected” cells remain colorless.

[0045]FIG. 6. Z-series imaging of corrected cells. Serial cross-sectionsof the HeLa cell represented in FIG. 5 are produced by Zeiss 510 LSMconfocal microscope revealing that the fusion protein is containedwithin the cell.

[0046]FIG. 7. Hygromycin-eGFP target plasmids. (A) PlasmidpAURHYG(ins)GFP contains a single base insertion mutation betweennucleotides 136 and 137, at codon 46, of the Hygromycin B codingsequence (cds) which is transcribed from the constitutive ADH1 promoter.The target sequence presented below indicates the deletion of an A andthe substitution of a C for a T directed by the oligonucleotides tore-establish the resistant phenotype. (B) Plasmid pAURHYG(rep)GFPcontains a base substitution mutation introducing a G at nucleotide 137,at codon 46, of the Hygromycin B coding sequence (cds). The targetsequence presented below the diagram indicates the amino acidconservative replacement of G with C, restoring gene function.

[0047]FIG. 8. Oligonucleotides for correction of hygromycin resistancegene. The sequence of the oligonucleotides used in experiments to assaycorrection of a hygromycin resistance gene are shown. DNA residues areshown in capital letters, RNA residues are shown in lowercase andnucleotides with a phosphorothioate backbone are capitalized andunderlined.

[0048]FIG. 9. pAURNeo(−)FIAsH plasmid. This figure describes the plasmidstructure, target sequence, oligonucleotides, and the basis fordetection of the gene alteration event by fluorescence.

[0049]FIG. 10. pYESHyg(×)eGFP plasmid. This plasmid is a constructsimilar to the pAURHyg(×)eGFP construct shown in FIG. 7, except thepromoter is the inducible GAL1 promoter. This promoter is inducible withgalactose, leaky in the presence of raffinose, and repressed in thepresence of dextrose.

[0050] The following examples are provided by way of illustration only,and are not intended to limit the scope of the invention disclosedherein.

EXAMPLE 1 Assay Method For Base Alteration And Preferred OligonucleotideSelection

[0051] In this example, single-stranded and double-hairpinoligonucleotides with chimeric backbones (see FIG. 1 for structures (Aand B) and sequences (C and D) of assay oligonucleotides) are used tocorrect a point mutation in the kanamycin gene of pK^(s)m4021 (FIG. 2)or the tetracycline gene of pT^(s)Δ208 (FIG. 3). All kanoligonucleotides share the same 25 base sequence surrounding the targetbase identified for change, just as all tet oligonucleotides do. Thesequence is given in FIGS. 1C and FIG. 1D. Each plasmid contains afunctional ampicillin gene. Kanamycin gene function is restored when a Gat position 4021 is converted to a C (via a substitution mutation);tetracycline gene function is restored when a deletion at position 208is replaced by a C (via frameshift mutation). A separate plasmid,pAURNeo(−)FIAsH (FIG. 9), bearing the kan^(s) gene is used in the cellculture experiments. This plasmid was constructed by inserting asynthetic expression cassette containing a neomycin phosphotransferase(kanamycin resistance) gene and an extended reading frame that encodes areceptor for the FIAsH ligand into the pAUR123 shuttle vector (PanveraCorp., Madison, Wis.). The resulting construct replicates in S.cerevisiae at low copy number, confers resistance to aureobasidinA andconstitutively expresses either the Neo+/FIAsH fusion product (afteralteration) or the truncated Neo−/FIAsH product (before alteration) fromthe ADH1 promoter. By extending the reading frame of this gene to codefor a unique peptide sequence capable of binding a small ligand to forma fluorescent complex, restoration of expression by correction of thestop codon can be detected in real time using confocal microscopy.Additional constructs can be made to test additional gene alterationevents.

[0052] We also construct three mammalian expression vectors,pHyg(rep)eGFP, pHyg(Δ)eGFP, pHyg(ins)eGFP, that contain a substitutionmutation at nucleotide 137 of the hygromycin-B coding sequence. (rep)indicates a T137→KG replacement, (Δ) represents a deletion of the G137and (ins) represents an A insertion between nucleotides 136 and 137. Allpoint mutations create a nonsense termination codon at residue 46. Weuse pHygEGFP plasmid (Invitrogen, Calif.) DNA as a template to introducethe mutations into the hygromycin-eGFP fusion gene by a two stepsite-directed mutagenesis PCR protocol. First, we generate overlapping5′ and a 3′ amplicons surrounding the mutation site by PCR for each ofthe point mutation sites. A 215 bp 5′ amplicon for the (rep), (Δ) or(ins) was generated by polymerization from oligonucleotide primerHygEGFPf (5′-AATACGACTCACTATAGG-3′) to primer Hygrepr(5′GACCTATCCACGCCCTCC-3′), HygΔr (5′-GACTATCCACGCCCTCC-3′), or Hyginsr(5′-GACATTATCCACGCCCTCC-3′), respectively. We generate a 300 bp 3′amplicon for the (rep), (Δ) or (ins) by polymerization fromoligonucleotide primers Hygrepf (5′-CTGGGATAGGTCCTGCGG-3′), HygΔf(5′-CGTGGATAGTCCTGCGG-3′), Hyginsf (5′-CGTGGATAATGTCCTGCGG-3′),respectively to primer HygEGFPr (5′-AAATCACGCCATGTAGTG-3′). We mix 20 ngof each of the resultant 5′ and 3′ overlapping amplicon mutation setsand use the mixture as a template to amplify a 523 bp fragment of theHygromycin gene spanning the KpnI and RsrII restriction endonucleasesites. We use the Expand PCR system (Roche) to generate all ampliconswith 25 cycles of denaturing at 94° C. for 10 seconds, annealing at 55°C. for 20 seconds and elongation at 68° C. for 1 minute. We digest 10 μgof vector pHygEGFP and 5 μg of the resulting fragments for each mutationwith KpnI and RsrII (NEB) and gel purify the fragment for enzymaticligation. We ligate each mutated insert into pHygEGFP vector at 3:1molar ration using T4 DNA ligase (Roche). We screen clones byrestriction digest, confirm the mutation by Sanger dideoxy chaintermination sequencing and purify the plasmid using a Qiagen maxiprepkit.

[0053] Oligonucleotide synthesis and cells. Chimeric oligonucleotidesand single-stranded oligonucleotides (including those with the indicatedmodifications) are synthesized using available phosphoramidites oncontrolled pore glass supports. After deprotection and detachment fromthe solid support, each oligonucleotide is gel-purified using, forexample, procedures such as those described in Gamper et al., Biochem.39, 5808-5816 (2000) and the concentrations determinedspectrophotometrically (33 or 40 μg/ml per A₂₆₀ unit of single-strandedor hairpin oligomer). HUH7 cells are grown in DMEM, 10% FBS, 2 mMglutamine, 0.5% pen/strep. The E.coli strain, DH10B, is obtained fromLife Technologies (Gaithersburg, Md.); DH10B cells contain a mutation inthe RECA gene (recA).

[0054] Cell-free extracts. We prepare cell-free extracts from HUH7 cellsor other mammalian cells, as follows. We employ this protocol withessentially any mammalian cell including, for example, H1299 cells(human epithelial carcinoma, non-small cell lung cancer), C127I(immortal murine mammary epithelial cells), MEF (mouse embryonicfibroblasts), HEC-1-A (human uterine carcinoma), HCT15 (human coloncancer), HCT116 (human colon carcinoma), LoVo (human colonadenocarcinoma), and HeLa (human cervical carcinoma). We harvestapproximately 2×10⁸ cells. We then wash the cells immediately in coldhypotonic buffer (20 mM HEPES, pH7.5; 5 mM KCl; 1.5 mM MgCl₂; 1 mM DTT)with 250 mM sucrose. We then resuspend the cells in cold hypotonicbuffer without sucrose and after 15 minutes we lyse the cells with 25strokes of a Dounce homogenizer using a tight fitting pestle. Weincubate the lysed cells for 60 minutes on ice and centrifuge the samplefor 15 minutes at 12000×g. The cytoplasmic fraction is enriched withnuclear proteins due to the extended co-incubation of the fractionsfollowing cell breakage. We then immediately aliquote and freeze thesupernatant at −80° C. We determine the protein concentration in theextract by the Bradford assay.

[0055] We also perform these experiments with cell-free extractsobtained from fungal cells, including, for example, S. cerevisiae(yeast), Ustilago maydis, and Candida albicans. For example, we growyeast cells into log phase in 2L YPD medium for 3 days at 30° C. We thencentrifuge the cultures at 5000×g, resuspend the pellets in a 10%sucrose, 50 mM Tris, 1 mM EDTA lysis solution and freeze them on dryice. After thawing, we add KCl, spermidine and lyticase to finalconcentrations of 0.25 mM, 5 mM and 0.1 mg/ml, respectively. We incubatethe suspension on ice for 60 minutes, add PMSF and Triton X100 to finalconcentrations of 0.1 mM and 0.1% and continue to incubate on ice for 20minutes. We centrifuge the lysate at 3000×g for 10 minutes to removelarger debris. We then remove the supernatant and clarify it bycentrifuging at 30000×g for 15 minutes. We then add glycerol to theclarified extract to a concentration of 10% (v/v) and freeze aliquots at−80° C. We determine the protein concentrabon of the extract by theBradford assay.

[0056] Reaction mixtures of 50 μl are used, consisting of 10-30 μgprotein of cell-free extract, which can be optionally substituted withpurified proteins or enriched fractions, about 1.5 μg chimericdouble-hairpin oligonucleotide or 0.55 μg single-stranded molecule(3S/25G or 6S/25G, see FIG. 1), and 1 μg of plasmid DNA (see FIGS. 2 and3) in a reaction buffer of 20 mM Tris, pH 7.4, 15 mM MgCl₂, 0.4 mM DTT,and 1.0 mM ATP. Reactions are initiated with extract and incubated at30° C. for 45 min. The reaction is stopped by placing the tubes on iceand then immediately deproteinized by two phenol/chloroform (1:1)extractions. Samples are then ethanol precipitated. The nucleic acid ispelleted at 15,000 r.p.m. at 4° C. for 30 min., is washed with 70%ethanol, resuspended in 50 μl H₂O, and is stored at −20° C. 5 μl ofplasmid from the resuspension (−100 ng) was transfected in 20 μl ofDH10B cells by electroporation (400 V, 300 μF, 4 kΩ) in a Cell-Poratorapparatus (Life Technologies). After electroporation, cells aretransferred to a 14 ml Falcon snap-cap tube with 2 ml SOC and shaken at37° C. for 1 h. Enhancement of final kan colony counts is achieved bythen adding 3 ml SOC with 10 μg/ml kanamycin and the cell suspension isshaken for a further 2 h at 37° C. Cells are then spun down at 3750×gand the pellet is resuspended in 500 μl SOC. 200 μl is added undilutedto each of two kanamycin (50 μg/ml) agar plates and 200 μl of a 10⁵dilution is added to an ampicillin (100 μg/ml) plate. After overnight37° C. incubation, bacterial colonies are counted using an Accucount1000 (Biologics). Gene conversion effectiveness is measured as the ratioof the average of the kan colonies on both plates per amp coloniesmultiplied by 10⁻⁵ to correct for the amp dilution.

[0057] The following procedure can also be used. 5 μl of resuspendedreaction mixtures (total volume 50 μl) are used to transform 20 μlaliquots of electro-competent ΔH10B bacteria using a Cell-Poratorapparatus (Life Technologies). The mixtures are allowed to recover in 1ml SOC at 37° C. for 1 hour at which time 50 μg/ml kanamycin or 12 μg/mltetracycline is added for an additional 3 hours. Prior to plating, thebacteria are pelleted and resuspended in 200 μl of SOC. 100 μl aliquotsare plated onto kan or tet agar plates and 100 μl of a 10⁻⁴ dilution ofthe cultures are concurrently plated on agar plates containing 100 μg/mlof ampicillin. Plating is performed in triplicate using sterile Pyrexbeads. Colony counts are determined by an Accu-count 1000 plate reader(Biologics). Each plate contains 200-500 ampicillin resistant coloniesor 0-500 tetracycline or kanamycin resistant colonies. Resistantcolonies are selected for plasmid extraction and DNA sequencing using anABI Prism kit on an ABI 310 capillary sequencer (PE Biosystems).

[0058] Chimeric single-stranded oligonucleotides. In FIG. 1 the upperstrands of chimeric oligonucleotides I and II are separated intopathways resulting in the generation of single-stranded oligonucleotidesthat contain (FIG. 1A) 2′-O-methyl RNA nucleotides or (FIG. 1B)phosphorothioate linkages. Fold changes in repair activity forcorrection of kan^(s) in the HUH7 cell-free extract are presented inparenthesis. Each single-stranded oligonucleotide is 25 bases in lengthand contains a G residue mismatched to the complementary sequence of thekan^(s) gene.

[0059] Molecules bearing 3, 6, 8, 10 and 12 phosphorothioate linkages inthe terminal regions at each end of a backbone with a total of 24linkages (25 bases) are tested in the kan^(s) system. Alternatively,molecules bearing 2, 4, 5, 7, 9 and 11 in the terminal regions at eachend are tested. The results of one such experiment, presented in Table 1and FIG. 1B, illustrate an enhancement of correction activity directedby some of these modified structures. In this illustrative example, themost efficient molecules contained 3 or 6 phosphorothioate linkages ateach end of the 25-mer; the activities are approximately equal(molecules IX and X with results of 3.09 and 3.7 respectively). Areduction in alteration activity may be observed as the number ofmodified linkages in the molecule is further increased. Interestingly, asingle-strand molecule containing 24 phosphorothioate linkages isminimally active suggesting that this backbone modification when usedthroughout the molecule supports only a low level of targeted generepair or alteration. Such a non-altering, completely modified moleculecan provide a baseline control for determining efficiency of correctionfor a specific oligonucleotide molecule of known sequence in definingthe optimum oligonucleotide for a particular alteration event.

[0060] The efficiency of gene repair directed byphosphorothioate-modified, single-stranded molecules, in a lengthdependent fashion, led us to examine the length of the RNA modificationused in the original chimera as it relates to correction. Construct Illrepresents the “RNA-containing” strand of chimera I and, as shown inTable 1 and FIG. 2A, it promotes inefficient gene repair. But, as shownin the same figure, reducing the RNA residues on each end from 10 to 3increases the frequency of repair. At equal levels of modification,however, 25-mers with 2′-O-methyl ribonucleotides were less effectivegene repair agents than the same oligomers with phosphorothioatelinkages. These results reinforce the fact that an RNA containingoligonucleotide is not as effective in promoting gene repair oralteration as a modified DNA oligonucleotide.

[0061] Repair of the kanamycin mutation requires a G→C exchange. Toconfirm that the specific desired correction alteration was obtained,colonies selected at random from multiple experiments are processed andthe isolated plasmid DNA is sequenced. As seen in FIG. 4, coloniesgenerated through the action of the single-stranded molecules 3S/25G(IX), 6S/25G (X) and 8S/25G (XI) respectively contained plasmidmolecules harboring the targeted base correction. While a few coloniesappeared on plates derived from reaction mixtures containing 25-merswith 10 or 12 thioate linkages on both ends, the sequences of theplasmid molecules from these colonies contain nonspecific base changes.In these illustrative examples, the second base of the codon is changed(see FIG. 3). These results show that modified single-strands can directgene repair, but that efficiency and specificity are reduced when the25-mers contain 10 or more phosphorothioate linkages at each end.

[0062] In FIG. 1, the numbers 3, 6, 8, 10, 12 and 12.5 respectivelyindicate how many phosphorothioate linkages (S) or 2′-O-methyl RNAnucleotides (R) are at each end of the examplified molecule althoughother molecules with 2, 4, 5, 7, 9 and 11 modifications at each end canalso be tested. Hence oligo 12S/25G represents a 25-mer oligonucleotidewhich contains 12 phosphorothioate linkages on each side of the centralG target mismatch base producing a fully phosphorothioate linkedbackbone, displayed as a dotted line. The dots are merely representativeof a linkage in the figure and do not depict the actual number oflinkages of the oligonucleotide. Smooth lines indicate DNA residues,wavy lines indicate 2′-O-methyl RNA residues and the carat indicates themismatched base site (G).

[0063] Correction of a mutant kanamycin gene in cultured mammaliancells. The experiments are performed using different mammalian cells,including, for example, 293 cells (transformed human primary kidneycells), HeLa cells (human cervical carcinoma), and H1299 (humanepithelial carcinoma, non-small cell lung cancer). HeLa cells are grownat 37° C. and 5% CO₂ in a humidified incubator to a density of 2×10⁵cells/ml in an 8 chamber slide (Lab-Tek). After replacing the regularDMEM with Optimem, the cells are co-transfected with 10 μg of plasmidpAURNeo(−)FIAsH and 5 μg of modified single-stranded oligonucleotide(3S/25G) that is previously complexed with 10 μg lipofectamine,according to the manufacturer's directions (Life Technologies). Thecells are treated with the liposome-DNA-oligo mix for 6 hrs at 37° C.Treated cells are washed with PBS and fresh DMEM is added. After a 16-18hr recovery period, the culture is assayed for gene repair. The sameoligonucleotide used in the cell-free extract experiments is used totarget transfected plasmid bearing the kan^(s) gene. Correction of thepoint mutation in this gene eliminates a stop codon and restores fullexpression. This expression can be detected by adding a smallnon-fluorescent ligand that bound to a C—C—R-E-C—C sequence in thegenetically modified carboxy terminus of the kan protein, to produce ahighly fluorescent complex (FIAsH system, Aurora BiosciencesCorporation). Following a 60 min incubation at room temperature with theligand (FIAsH-EDT2), cells expressing full length kan product acquire anintense green fluorescence detectable by fluorescence microscopy using afluorescein filter set. Similar experiments are performed using theHygeGFP target as described in Example 2 with a variety of mammaliancells, including, for example, COS-1 and COS-7 cells (African greenmonkey), and CHO-K1 cells (Chinese hamster ovary). The experiments arealso performed with PG12 cells (rat pheochromocytoma) and ES cells(human embryonic stem cells).

[0064] Summary of experimental results. Tables 1, 2 and 3 respectivelyprovide data on the efficiency of gene repair directed bysingle-stranded oligonucleotides. Table 1 presents data using acell-free extract from human liver cells (HUH7) to catalyze repair ofthe point mutation in plasmid pkan^(s)m4021 (see FIG. 1). Table 2illustrates that the oligomers are not dependent on MSH2 or MSH3 foroptimal gene repair activity. Table 3 illustrates data from the repairof a frameshift mutation (FIG. 3) in the tet gene contained in plasmidpTetΔ208. Table 4 illustrates data from repair of the pkan^(s)m4021point mutation catalyzed by plant cell extracts prepared from canola andmusa (banana). Colony numbers are presented as kan^(r) or tet^(r) andfold increases (single strand versus double hairpin) are presented forkan^(r) in Table 1.

[0065]FIG. 5A is a confocal picture of HeLa cells expressing thecorrected fusion protein from an episomal target. Gene repair isaccomplished by the action of a modified single-stranded oligonucleotidecontaining 3 phosphorothioate linkages at each end (3S/25G). FIG. 5Brepresents a “Z-series” of HeLa cells bearing the corrected fusion gene.This series sections the cells from bottom to top and illustrates thatthe fluorescent signal is “inside the cells”.

[0066] Results. In summary, we have designed a novel class ofsingle-stranded oligonucleotides with backbone modifications at thetermini and demonstrate gene repair/conversion activity in mammalian andplant cell-free extracts. We confirm that the all DNA strand of theRNA-DNA double-stranded double hairpin chimera is the active componentin the process of gene repair. In some cases, the relative frequency ofrepair by the novel oligonucleotides of the invention is elevatedapproximately 3-4-fold when compared to frequencies directed by chimericRNA-DNA double hairpin oligonucleotides.

[0067] This strategy centers around the use of extracts from varioussources to correct a mutation in a plasmid using a modifiedsingle-stranded or a chimeric RNA-DNA double hairpin oligonucleotide. Amutation is placed inside the coding region of a gene conferringantibiotic resistance in bacteria, here kanamycin or tetracycline. Theappearance of resistance is measured by genetic readout in E.coli grownin the presence of the specified antibiotic. The importance of thissystem is that both phenotypic alteration and genetic inheritance can bemeasured. Plasmid pK^(s)m4021 contains a mutation (T→G) at residue 4021rendering it unable to confer antibiotic resistance in E.coli. Thispoint mutation is targeted for repair by oligonucleotides designed torestore kanamycin resistance. To avoid concerns of plasmid contaminationskewing the colony counts, the directed correction is from G→C ratherthan G→T (wild-type). After isolation, the plasmid is electroporatedinto the DH10B strain of E.coli, which contains inactive RecA protein.The number of kanamycin colonies is counted and normalized byascertaining the number of ampicillin colonies, a process that controlsfor the influence of electroporation. The number of colonies generatedfrom three to five independent reactions was averaged and is presentedfor each experiment. A fold increase number is recorded to aid incomparison.

[0068] The original RNA-DNA double hairpin chimera design, e.g., asdisclosed in U.S. Pat. No. 5,565,350, consists of two hybridized regionsof a single-stranded oligonucleotide folded into a double hairpinconfiguration. The double-stranded targeting region is made up of a 5base pair DNA/DNA segment bracketed by 10 base pair RNA/DNA segments.The central base pair is mismatched to the corresponding base pair inthe target gene. When a molecule of this design is used to correct thekan^(s) mutation, gene repair is observed (I in FIG. 1A). Chimera II(FIG. 1B) differs partly from chimera I in that only the DNA strand ofthe double hairpin is mismatched to the target sequence. When thischimera was used to correct the kan^(s) mutation, it was twice asactive. In the same study, repair function could be further increased bymaking the targeting region of the chimera a continuous RNA/DNA hybrid.

[0069] Frame shift mutations are repaired. By using plasmid pT^(s)Δ208,described in FIG. 1(C) and FIG. 3, the capacity of the modifiedsingle-stranded molecules that showed activity in correcting a pointmutation, can be tested for repair of a frameshift. To determineefficiency of correction of the mutation, a chimeric oligonucleotide(Tet I), which is designed to insert a T residue at position 208, isused. A modified single-stranded oligonucleotide (Tet IX) directs theinsertion of a T residue at this same site. FIG. 3 illustrates theplasmid and target bases designated for change in the experiments. Whenall reaction components are present (extract, plasmid, oligomer),tetracycline resistant colonies appear. The colony count increases withthe amount of oligonucleotide used up to a point beyond which the countfalls off (Table 3). No colonies above background are observed in theabsence of either extract or oligonucleotide, nor when a modifiedsingle-stranded molecule bearing perfect complementarity is used. FIG. 3represents the sequence surrounding the target site and shows that a Tresidue is inserted at the correct site. We have isolated plasmids fromfifteen colonies obtained in three independent experiments and eachanalyzed sequence revealed the same precise nucleotide insertion. Thesedata suggest that the single-stranded molecules used initially for pointmutation correction can also repair nucleotide deletions.

[0070] Comparison of phosphorothioate oligonucleotides to 2′-O-methylsubstituted oligonucleotides. From a comparison of molecules VII and XI,it is apparent that gene repair is more subject to inhibition by RNAresidues than by phosphorothioate linkages. Thus, even though both ofthese oligonucleotides contain an equal number of modifications toimpart nuclease resistance, XI (with 16 phosphorothioate linkages) hasgood gene repair activity while VII (with 16 2′-O-methyl RNA residues)is inactive. Hence, the original chimeric double hairpin oligonucleotideenabled correction directed, in large part, by the strand containing alarge region of contiguous DNA residues.

[0071] Oligonucleotides can target multiple nucleotide alterationswithin the same template. The ability of individual single-strandedoligonucleotides to correct multiple mutations in a single targettemplate is tested using the plasmid pK^(s)m4021 and the followingsingle-stranded oligonucleotides modified with 3 phosphorothioatelinkages at each end (indicated as underlined nucleotides): Oligol is a25-mer with the sequence TTCGATAAGCCTATGCTGACCCGTG corrects the originalmutation present in the kanamycin resistance gene of pK^(s)m4021 as wellas directing another alteration 2 basepairs away in the target sequence(both indicated in boldface); Oligo2 is a 70-mer with the 5′-endsequence TTCGGCTACGACTGGGCACAACAGACAATTGGC with the remainingnucleotides being completely complementary to the kanamycin resistancegene and also ending in 3 phosphorothioate linkages at the 3′ end.Oligo2 directs correction of the mutation in pK^(s)m4021 as well asdirecting another alteration 21 basepairs away in the target sequence(both indicated in boldface).

[0072] We also use additional oligonucleotides to assay the ability ofindividual oligonucleotides to correct multiple mutations in thepK^(s)M4021 plasmid. These include, for example, a second 25-mer thatalters two nucleotides that are three nucleotides apart with thesequence 5′-TTGTGCCCAGTCGTATCCGAATAGC-3′; a 70-mer that alters twonucleotides that are 21 nucleotides apart with the sequence5′-CATCAGAGCAGCCAATTGTCTGTTGTGCCCAGTCGTAGCCGAATAGCCTCTCCACCCAAGCGGCCGGAGA-3′;and another 70-mer that alters two nucleotides that are 21 nucleotidesapart with the sequence5′-GCTGACAGCCGGAACACGGCGGCATCAGAGCAGCCAATTGTCTGTTGTGCCCAGTCGTAGCCGAATAGCCT-3′.The nucleotides in the oligonucleotides that direct alteration of thetarget sequence are underlined and in boldface. These oligonucleotidesare modified in the same way as the other oligonucleotides of theinvention.

[0073] We assay correction of the original mutation in pK^(s)m4021 bymonitoring kanamycin resistance (the second alterations which aredirected by Oligo2 and Oligo3 are silent with respect to the kanamycinresistance phenotype). In addition, in experiments with Oligo2, we alsomonitor cleavage of the resulting plasmids using the restriction enzymeTsp509I which cuts at a specific site present only when the secondalteration has occurred (at ATT in Oligo2). We then sequence theseclones to determine whether the additional, silent alteration has alsobeen introduced. The results of an analysis are presented below: Oligo1(25-mer) Oligo2 (70-mer) Clones with both sites changed 9 7 Clones witha single site changed 0 2 Clones that were not changed 4 1

[0074] Nuclease sensitivity of unmodified DNA oligonucleotide.Electrophoretic analysis of nucleic acid recovered from the cell-freeextract reactions conducted here confirm that the unmodifiedsingle-stranded 25-mer did not survive incubation whereas greater than90% of the terminally modified oligos did survive (as judged byphoto-image analyses of agarose gels).

[0075] Plant extracts direct repair. The modified single-strandedconstructs can be tested in plant cell extracts. We have observed genealteration using extracts from multiple plant sources, including, forexample, Arabidopsis, tobacco, banana, maize, soybean, canola, wheat,spinach as well as spinach chloroplast extract We prepare the extractsby grinding plant tissue or cultured cells under liquid nitrogen with amortar and pestle. We extract 3 ml of the ground plant tissue with 1.5ml of extraction buffer (20 mM HEPES, pH7.5; 5 mM Kcl; 1.5 mM MgCl₂; 10mM DTT; 10% [v/v] glycerol; and 1% [w/v] PVP). We then homogenize thesamples with 15 strokes of a Dounce homogenizer. Followinghomogenization, we incubate the samples on ice for 1 hour and centrifugeat 3000×g for 5 minutes to remove plant cell debris. We then determinethe protein concentration in the supernatants (extracts) by Bradfordassay. We dispense 100 μg (protein) aliquots of the extracts which wefreeze in a dry ice-ethanol bath and store at −80° C.

[0076] We describe experiments using two sources here: a dicot (canola)and a monocot (banana, Musa acuminata cv. Rasthali). Each vector directsgene repair of the kanamycin mutation (Table 4); however, the level ofcorrection is elevated 2-3 fold relative to the frequency observed withthe chimeric oligonucleotide. These results are similar to thoseobserved in the mammalian system wherein a significant improvement ingene repair occurred when modified single-stranded molecules were used.

[0077] Tables are attached hereto. TABLE 1 Gene repair activity isdirected by single-stranded oligonucleotides.

[0078] Plasmid pK^(s)m4021 (1 μg), the indicated oligonucleotide (1.5 μgchimeric oligonucleotide or 0.55 μg single-stranded oligonucleotide;molar ratio of oligo to plasmid of 360 to 1) and either 10 or 20 μg ofHUH7 cell-free extract were incubated 45 min at 37° C. Isolated plasmidDNA was electroporated into E. coli (strain DH10B) and the number ofkan^(r) colonies counted. The data represent the number of kanamycinresistant colonies per 10⁶ ampicillin resistant colonies generated fromthe same reaction and is the average of three experiments (standarddeviation usually less than +/−15%). Fold increase is defined relativeto 418 kan^(r) colonies (second reaction) and in all reactions wascalculated using the 20 μg sample. TABLE II Modified single-strandedoligomers are not dependent on MSH2 or MSH3 for optimal gene repairactivity.

[0079] Chimeric oligonucleotide (1.5 μg) or modified single-strandedoligonucleotide (0.55 μg) was incubated with 1 μg of plasmid pK^(s)m4021and 20 μg of the indicated extracts. MEF represents mouse embryonicfibroblasts with either MSH2 (2^(−/−)) or MSH3 (3^(−/−)) deleted.MEF^(+/+) indicates wild-type mouse embryonic fibroblasts. The otherreaction components were then added and processed through the bacterialreadout system. The data represent the number of kanamycin resistantcolonies per 10⁶ ampicillin resistant colonies. TABLE III Frameshiftmutation repair is directed by single-stranded oligonucleotides

[0080] Each reaction mixture contained the indicated amounts of plasmidand oligonucleotide. The extract used for these experiments came fromHUH7 cells. The data represent the number of tetracycline resistantcolonies per 10⁶ ampicillin resistant colonies generated from the samereaction and is the average of 3 independent experiments. Tet I is achimeric oligonucleotide and Tet IX is a modified single-strandedoligonucleotide that are designed to insert a T residue at position 208of pT^(s)Δ208. These oligonucleotides are equivalent to structures I andIX in FIG. 2. TABLE IV Plant cell-free extracts support gene repair bysingle-stranded oligonucleotides

[0081] Canola or Musa cell-free extracts were tested for gene repairactivity on the kanamycin-sensitive gene as previously described in(18). Chimeric oligonucleotide II (1.5 μg) and modified single-strandedoligonucleotides IX and X (0.55 μg) were used to correct pK^(s)m4021.Total number of kan^(r) colonies are present per 10⁷ ampicillinresistant colonies and represent an average of four independentexperiments. TABLE V Gene repair activity in cell-free extracts preparedfrom yeast (Saccharomyces cerevisiae)

EXAMPLE 2 Yeast Cell Targeting Assay Method for Base Alteration andPreferred Oligonucleotide Selection

[0082] In this example, single-stranded oligonucleotides with modifiedbackbones and double-hairpin oligonucleotides with chimeric, RNA-DNAbackbones are used to measure gene repair using two episomal targetswith a fusion between a hygromycin resistance gene and eGFP as a targetfor gene repair. These plasmids are pAURHYG(rep)GFP, which contains apoint mutation in the hygromycin resistance gene (FIG. 7),pAURHYG(ins)GFP, which contains a single-base insertion in thehygromycin resistance gene (FIG. 7) and pAURHYG(Δ)GFP which has a singlebase deletion. We also use the plasmid containing a wild-type copy ofthe hygromycin-eGFP fusion gene, designated pAURHYG(wt)GFP, as acontrol. These plasmids also contain an aureobasidinA resistance gene.In pAURHYG(rep)GFP, hygromycin resistance gene function and greenfluorescence from the eGFP protein are restored when a G at position137, at codon 46 of the hygromycin B coding sequence, is converted to aC thus removing a premature stop codon in the hygromycin resistance genecoding region. In pAURHYG(ins)GFP, hygromycin resistance gene functionand green fluorescence from the eGFP protein are restored when an Ainserted between nucleotide positions 136 and 137, at codon 46 of thehygromycin B coding sequence, is deleted and a C is substituted for theT at position 137, thus correcting a frameshift mutation and restoringthe reading frame of the hygromycin-eGFP fusion gene.

[0083] We synthesize the set of three yeast expression constructspAURHYG(rep)eGFP, pAURHYG(Δ)eGFP, pAURHYG(ins)eGFP, that contain a pointmutation at nucleotide 137 of the hygromycin-B coding sequence asfollows. (rep) indicates a T137→G replacement, (Δ) represents a deletionof the G137 and (ins) represents an A insertion between nucleotides 136and 137. We construct this set of plasmids by excising the respectiveexpression cassettes by restriction digest from pHyg(×)EGFP and ligationinto pAUR123 (Panvera, Calif.). We digest 10 μg pAUR123 vector DNA, aswell as, 10 μg of each pHyg(×)EGFP construct with KpnI and SaII (NEB).We gel purify each of the DNA fragments and prepare them for enzymaticligation. We ligate each mutated insert into pHygEGFP vector at 3:1molar ration using T4 DNA ligase (Roche). We screen clones byrestriction digest, confirm by Sanger dideoxy chain terminationsequencing and purify using a Qiagen maxiprep kit.

[0084] We use this system to assay the ability of five oligonucleotides(shown in FIG. 8) to support correction under a variety of conditions.The oligonucleotides which direct correction of the mutation inpAURHYG(rep)GFP can also direct correction of the mutation inpAURHYG(ins)GFP. Three of the four oligonucleotides (HygE3T/25,HygE3T/74 and HygGG/Rev) share the same 25-base sequence surrounding thebase targeted for alteration. HygGG/Rev is an RNA-DNA chimeric doublehairpin oligonucleotide of the type described in the prior art. One ofthese oligonucleotides, HygE3T/74, is a 74-base oligonucleotide with the25-base sequence centrally positioned. The fourth oligonucleotide,designated HygE3T/74α, is the reverse complement of HygE3T/74. The fiftholigonucleotide, designated Kan70T, is a non-specific, controloligonucleotide which is not complementary to the target sequence.Alternatively, an oligonucleotide of identical sequence but lacking amismatch to the target or a completely thioate modified oligonucleotideor a completely 2-0-methylated modified oligonucleotide may be used as acontrol.

[0085] Oligonucleotide synthesis and cells. We synthesized and purifiedthe chimeric, double-hairpin oligonucleotides and single-strandedoligonucleotides (including those with the indicated modifications) asdescribed in Example 1. Plasmids used for assay were maintained stablyin yeast (Saccharomyces cerevisiae) strain LSY678 MATα at low copynumber under aureobasidin selection. Plasmids and oligonucleotides areintroduced into yeast cells by electroporation as follows: to prepareelectrocompetent yeast cells, we inoculate 10 ml of YPD media from asingle colony and grow the cultures overnight with shaking at 300 rpm at30° C. We then add 30 ml of fresh YPD media to the overnight culturesand continue shaking at 30° C. until the OD₆₀₀ was between 0.5 and 1.0(3-5 hours). We then wash the cells by centrifuging at 4° C. at 3000 rpmfor 5 minutes and twice resuspending the cells in 25 ml ice-colddistilled water. We then centrifuge at 4° C. at 3000 rpm for 5 minutesand resuspend in 1 ml ice-cold 1M sorbitol and then finally centrifugethe cells at 4° C. at 5000 rpm for 5 minutes and resuspend the cells in120 μl 1M sorbitol. To transform electrocompetent cells with plasmids oroligonucleotides, we mix 40 μl of cells with 5 μg of nucleic acid,unless otherwise stated, and incubate on ice for 5 minutes. We thentransfer the mixture to a 0.2 cm electroporation cuvette andelectroporate with a BIO-RAD Gene Pulser apparatus at 1.5 kV, 25 μF, 200Ω for one five-second pulse. We then immediately resuspend the cells in1 ml YPD supplemented with 1M sorbitol and incubate the cultures at 30°C. with shaking at 300 rpm for 6 hours. We then spread 200 μl of thisculture on selective plates containing 300 μg/ml hygromycin and spread200 μl of a 10⁵ dilution of this culture on selective plates containing500 ng/ml aureobasidinA and/or and incubate at 30° C. for 3 days toallow individual yeast colonies to grow. We then count the colonies onthe plates and calculate the gene conversion efficiency by determiningthe number of hygromycin resistance colonies per 10⁵ aureobasidinAresistant colonies.

[0086] Frameshift mutations are repaired in yeast cells. We test theability of the oligonucleotides shown in FIG. 8 to correct a frameshiftmutation in vivo using LSY678 yeast cells containing the plasmidpAURHYG(ins)GFP. These experiments, presented in Table 6, indicate thatthese oligonucleotides can support gene correction in yeast cells. Thesedata reinforce the results described in Example 1 indicating thatoligonucleotides comprising phosphorothioate linkages facilitate genecorrection much more efficiently than control duplex, chimeric RNA-DNAoligonucleotides. This gene correction activity is also specific astransformation of cells with the control oligonucleotide Kan70T producedno hygromycin resistant colonies above background and thus Kan70T didnot support gene correction in this system. In addition, we observe thatthe 74base oligonucleotide (HygE3T/74) corrects the mutation inpAURHYG(ins)GFP approximately five-fold more efficiently than the25-base oligonucleotide (HygE3T/25). We also perform control experimentswith LSY678 yeast cells containing the plasmid pAURHYG(wt)GFP. With thisstrain we observed that even without added oligonucleotides, there aretoo many hygromycin resistant colonies to count.

[0087] We also use additional oligonucleotides to assay the ability ofindividual oligonucleotides to correct multiple mutations in thepAURHYG(×)eGFP plasmid. These include, for example, one that alters twobasepairs that are 3 nucleotides apart is a 74-mer with the sequence5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGGTACGTCCTGCGGGTAAATAGCTGCGCCGATGGTTTCTAC-3′;a 74-mer that alters two basepairs that are 15 nucleotides apart withthe sequence5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGATACGTCCTGCGGGTAAACAGCTGCGCCGATGGTTTCTAC-3′;and a 74-mer that alters two basepairs that are 27 nucleotides apartwith the sequence5′-CTCGTGCTTTCAGCTTCGATGTAGGAGGGCGTGGATACGTCCTGCGGGTAAATAGCTGCGCCGACGGTTTCTAC.The nucleotides in these oligonucleotides that direct alteration of thetarget sequence are underlined and in boldface. These oligonucleotidesare modified in the same ways as the other oligonucleotides of theinvention.

[0088] Oligonucleotides targeting the sense strand direct genecorrection more efficiently. We compare the ability of single-strandedoligonucleotides to target each of the two strands of the targetsequence of both pAURHYG(ins)GFP and pAURHYG(rep)GFP. These experiments,presented in Tables 7 and 8, indicate that an oligonucleotide,HygE3T/74α, with sequence complementary to the sense strand (i.e. thestrand of the target sequence that is identical to the mRNA) of thetarget sequence facilitates gene correction approximately ten-fold moreefficiently than an oligonucleotide, HygE3T/74, with sequencecomplementary to the non-transcribed strand which serves as the templatefor the synthesis of RNA. As indicated in Table 7, this effect wasobserved over a range of oligonucleotide concentrations from 0-3.6 μg,although we did observe some variability in the difference between thetwo oligonucleotides (indicated in Table 7 as a fold difference betweenHygE3T/74α and HygE3T/74). Furthermore, as shown in Table 8, we observeincreased efficiency of correction by HygE3T/74α relative to HygE3T/74regardless of whether the oligonucleotides were used to correct the basesubstitution mutation in pAURHYG(rep)GFP or the insertion mutation inpAURHYG(ins)GFP. The data presented in Table 8 further indicate that thesingle-stranded oligonucleotides correct a base substitution mutationmore efficiently than an insertion mutation. However, this last effectwas much less pronounced and the oligonucleotides of the invention areclearly able efficiently to correct both types of mutations in yeastcells. In addition, the role of transcription is investigated usingplasmids with inducible promoters such as that described in FIG. 10.

[0089] Optimization of oligonucleotide concentration. To determine theoptimal concentration of oligonucleotide for the purpose of genealteration, we test the ability of increasing concentrations ofHyg3T/74α to correct the mutation in pAURHYG(rep)GFP contained in yeastLSY678. We chose this assay system because our previous experimentsindicated that it supports the highest level of correction. However,this same approach could be used to determine the optimal concentrationof any given oligonucleotide. We test the ability of Hyg3T/74α tocorrect the mutation in pAURHYG(rep)GFP contained in yeast LSY678 over arange of oligonucleotide concentrations from 0-10.0 μg. As shown inTable 9, we observe that the correction efficiency initially increaseswith increasing oligonucleotide concentration, but then declines at thehighest concentration tested.

[0090] Tables are attached hereto. TABLE 6 Correction of an insertionmutation in pAURHYG(ins)GFP by HygGG/Rev, HygE3T/25 and HygE3T/74Oligonucleotide Colonies on Colonies on Correction Tested HygromycinAureobasidin (/10⁵) Efficiency HygGG/Rev 3 157 0.02 HygE3T/25 64 1470.44 HygE3T/74 280 174 1.61 Kan70T 0 — —

[0091] TABLE 7 An oligonucleotide targeting the sense strand of thetarget sequence corrects more efficiently. Amount of Colonies perhygromycin plate Oligonucleotide (μg) HygE3T/74 HygE3T/74α 0 0 0 0.6 24128 (8.4x)* 1.2 69 140 (7.5x)* 2.4 62 167 (3.8x)* 3.6 29 367 (15x)* 

[0092] TABLE 8 Correction of a base substitution mutation is moreefficient than correction of a frame shift mutation. OligonucleotidePlasmid tested (contained in LSY678) Tested (5 μg) pAURHYG(ins)GFPpAURHYG(rep)GFP HygE3T/74 72 277 HygE3T/74α 1464 2248 Kan70T 0 0

[0093] TABLE 9 Optimization of oligonucleotide concentration inelectroporated yeast cells. Colonies on Colonies on Correction Amount(μg) hygromycin aureobasidin (/10⁵) efficiency 0 0 67 0 1.0 5 64 0.082.5 47 30 1.57 5.0 199 33 6.08 7.5 383 39 9.79 10.0 191 33 5.79

EXAMPLE 3 Cultured Cell Manipulation

[0094] Mononuclear cells are isolated from human umbilical cord blood ofnormal donors using Ficoll Hypaque (Pharmacia Biotech, Uppsala, Sweden)density centrifugation. CD34+ cells are immunomagnetically purified frommononuclear cells using either the progenitor or Multisort Kits(Miltenyi Biotec, Auburn, Calif.). Lin⁻CD38⁻ cells are purified from themononuclear cells using negative selection with StemSep system accordingto the manufacturer's protocol (Stem Cell Technologies, Vancouver,Calif.). Cells used for microinjection are either freshly isolated orcryopreserved and cultured in Stem Medium (S Medium) for 2 to 5 daysprior to microinjection. S Medium contains Iscoves' Modified Dulbecco'sMedium without phenol red (IMDM) with 100 μg/mlglutamine/penicillin/streptomycin, 50 mg/ml bovine serum albumin, 50μg/ml bovine pancreatic insulin, 1 mg/ml human transferrin, and IMDM;Stem Cell Technologies), 40 μg/ml low-density lipoprotein (LDL; Sigma,St. Louis, Mo.), 50 mM HEPEs buffer and 50 μM 2-mercaptoethanol, 20ng/ml each of thrombopoietin, fit-3 ligand, stem cell factor and humanIL-6 (Pepro Tech Inc., Rocky Hill, N.J.). After microinjection, cellsare detached and transferred in bulk into wells of 48 well plates forculturing.

[0095] 35 mm dishes are coated overnight at 40° C. with 50 μg/miFibronectin (FN) fragment CH-296 (Retronectin; TaKaRa Biomedicals,Panvera, Madison, Wis.) in phosphate buffered saline and washed withIMDM containing glutamine/penicillin/streptomycin. 300 to 2000 cells areadded to cloning rings and attached to the plates for 45 minutes at 37°C. prior to microinjection. After incubation, cloning rings are removedand 2 ml of S Medium are added to each dish for microinjection. Pulledinjection needles with a range of 0.22μ to 0.3μ outer tip diameter areused. Cells are visualized with a microscope equipped with a temperaturecontrolled stage set at 37° C. and injected using an electronicallyinterfaced Eppendorf Micromanipulator and Transjector. Successfullyinjected cells are intact, alive and remain attached to the plate postinjection. Molecules that are flourescenty labeled allow determinationof the amount of oligonucleotide delivered to the cells.

[0096] For in vitro erythropoiesis from Lin⁻CD38⁻ cells, the procedureof Malik, 1998 can be used. Cells are cultured in ME Medium for 4 daysand then cultured in E Medium for 3 weeks. Erythropoiesis is evident byglycophorin A expression as well as the presence of red colorrepresenting the presence of hemoglobin in the cultured cells. Theinjected cells are able to retain their proliferative capacity and theability to generate myeloid and erythoid progeny. CD34+ cells canconvert a normal A (β^(A)) to sickle T (β^(s)) mutation in the β-globingene or can be altered using any of the oligonucleotides of theinvention herein for correction or alteration of a normal gene to amutant gene. Alternatively, stem cells can be isolated from blood ofhumans having genetic disease mutations and the oligonucleotides of theinvention can be used to correct a defect or to modify genomes withinthose cells.

[0097] Alternatively, non-stem cell populations of cultured cells can bemanipulated using any method known to those of skill in the artincluding, for example, the use of polycations, cationic lipids,liposomes, polyethylenimine (PEI), electroporation, biolistics, calciumphophate precipitation, or any other method known in the art

Notes on the Tables Presented Below

[0098] Each of the following tables presents, for the specified humangene, a plurality of mutations that are known to confer aclinically-relevant phenotype and, for each mutation, theoligonucleotides that can be used to correct the respective mutationsite-specifically in the human genome according to the presentinvention.

[0099] The left-most column identifies each mutation and the clinicalphenotype that the mutation confers.

[0100] For most entries, the mutation is identified at both the nucleicacid and protein level. At the amino acid level, mutations are presentedaccording to the following standard nomenclature. The centered numberidentifies the position of the mutated codon in the protein sequence; tothe left of the number is the wild type residue and to the right of thenumber is the mutant codon. Codon numbering is according to the HumanGene Mutation Database, Cardiff, Wales, UK(http://archive.uwcm.ac.uk/search/mg/allgenes). Terminator codons areshown as “TERM”. At the nucleic acid level, the entire triplet of thewild type and mutated codons is shown.

[0101] The middle column presents, for each mutation, fouroligonucleotides capable of repairing the mutation site-specifically inthe human genome or in cloned human DNA including human DNA inartificial chromosomes, episomes, plasmids, or other types of vectors.The oligonucleotides of the invention, however, may include any of theoligonucleotides sharing portions of the sequence of the 121 basesequence. Thus, oligonucleotides of the invention for each of thedepicted targets may be 18, 19, 20 up to about 121 nucleotides inlength. Sequence may be added non-symmetrically.

[0102] All oligonucleotides are presented, per convention, in the 5′ to3′ orientation. The nucleotide that effects the change in the genome isunderlined and presented in bold.

[0103] The first of the four oligonucleotides for each mutation is a 121nt oligonucleotide centered about the repair nucleotide. The secondoligonucleotide, its reverse complement, targets the opposite strand ofthe DNA duplex for repair. The third oligonucleotide is the minimal 17nt domain of the first oligonucleotide, also centered about the repairnucleotide. The fourth oligonucleotide is the reverse complement of thethird, and thus represents the minimal 17 nt domain of the second.

[0104] The third column of each table presents the SEQ ID NO: of therespective repair oligonucleotide.

EXAMPLE 4 Adenosine Deaminase (ADA)

[0105] Adenosine deaminase (ADA, EC 3.5.4.4) catalyses the deaminationof adenosine and 2′-deoxyadenosine to inosine or 2′-deoxyinosinerespectively. ADA deficiency has been identified as the metabolic basisfor 20-30% of cases with recessively inherited severe combinedimmunodeficiency (SCID). Affected infants are subject to recurrentchronic viral, fungal, protozoal, and bacterial infections andfrequently present with persistent diarrhea, failure to thrive andcandidiasis. In patents homozygous for ADA deficiency, 2′-deoxyadenosineaccumulating during the rapid turnover of cells rich in DNA is convertedback to dATP, either by adenosine kinase or deoxycytidine kinase. Manyhypotheses have been advanced to explain the specific toxicity to theimmune system in ADA deficiency. The apparently selective accumulationof dATP in thymocytes and peripheral blood B cells, with resultantinhibition of ribonucleotide reductase and DNA synthesis is probably theprincipal mechanism.

[0106] The structural gene for ADA is encoded as a single 32 kb locuscontaining 12 exons. Studies of the molecular defect in ADA-deficientpatents have shown that mRNA is usually detectable in normal orsupranormal amounts. Specific base substitution mutations have beendetected in the majority of cases with the complete deficiency. A C-to-Tbase substitution mutation in exon 11 accounts for a high proportion ofthese, whilst a few patents are homozygous for large deletionsencompassing exon I. A common point mutation resulting in a heat-labileADA has been characterised in some patients with partial ADA deficiency,a disorder with an apparently increased prevalence in the Caribbean.

[0107] As yet no totally effective therapy for ADA deficiency has beenreported, except in those few cases where bone marrow from an HLA/MLRcompatible sibling donor was available.

[0108] Two therapeutic approaches have provided long-term benefit inspecific instances. First, reconstitution using T cell depletedmismatched sibling marrow has been encouraging, particularly in earlypresenters completely deficient in ADA. Secondly, therapy withpolyethylene glycol-modified adenosine deaminase (PEG-ADA) for more than5 years has produced a sustained increase in lymphocyte numbers andmitogen responses together with evidence of in vivo B cell function.Success has generally been achieved in late presenters with residual ADAactivity in mononuclear cells.

[0109] ADA deficiency has been chosen as the candidate disease for genereplacement therapy and the first human experiment commenced in 1990.The clinical consequences of overexpression of ADA activity—one of thepotential hazards of gene implant—are known and take the form of anhereditary haemolytic anaemia associated with a tissue-specific increasein ADA activity. The genetic basis for the latter autosomal dominantdisorder seemingly relates to markedly increased levels of structurallynormal ADA mRNA. TABLE 10 ADA Mutations and Genome-Correcting OligosClinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Adenosinedeaminase AGAGACCCACCGAGCGGCGGCGGAGGGAGCAGCGCCGGGG 1 deficiencyCGCACGAGGGCACCATGGCC C AGACGCCCGCCTTCGACAAG GLN3TERMCCCAAAGTGAGCGCGCGCGGGGGCTCCGGGGACGGGGGTC CAG to TAGGACCCCCGTCCCCGGAGCCCCCGCGCGCGCTCACTTTGGG 2 CTTGTCGAAGGCGGGCGTCT GGGCCATGGTGCCCTCGTGCG CCCCGGCGCTGCTCCCTCCGCCGCCGCTCGGTGGGTCTCT CCATGGCC CAGACGCCC 3 GGGCGTCT G GGCCATGG 4 Adenosine deaminaseTATTTGTTCTCTCTCTCCCTTTCTCTCTCTCTTCCCCCTGCCC 5 deficiencyCCTTGCAGGTAGAACTG C ATGTCCACCTAGACGGATCCATCA HIS15ASPAGCCTGAAACCATCTTATACTATGGCAGGTAAGTCC CAT to GATGGACTTACCTGCCATAGTATAAGATGGTTTCAGGCTTGATGGA 6 TCCGTCTAGGTGGACAT GCAGTTCTACCTGCAAGGGGGCAG GGGGAAGAGAGAGAGAAAGGGAGAGAGAGAACAAATA TAGAACTG CATGTCCAC 7 GTGGACAT G CAGTTCTA 8 Adenosine deaminaseTCCCTTTCTCTCTCTCTTCCCCCTGCCCCCTTGCAGGTAGAA 9 deficiencyCTGCATGTCCACCTAGAC G GATCCATCAAGCCTGAAACCATC GLY20ARGTTATACTATGGCAGGTAAGTCCATACAGAAGAGCCCT GGA to AGAAGGGCTCTTCTGTATGGACTTACCTGCCATAGTATAAGATGGT 10 TTCAGGCTTGATGGATC CGTCTAGGTGGACATGCAGTTCTAC CTGCAAGGGGGCAGGGGGAAGAGAGAGAGAAAGGGA ACCTAGAC GGATCCATC 11 GATGGATC C GTCTAGGT 12 Adenosine deaminaseCCTGGAGCTCCCAAGGGACTTGGGGAAGGTTGTTCCCAACC 13 deficiencyCCTTTCTTCCCTTCCCAGG G GCTGCCGGGAGGCTATCAAAAG GLY74CYSGACGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGG GGC to TGCCCTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCCTTTT 14 GATAGCCTCCCGGCAGC CCCTGGGAAGGGAAGAAAGGGGTT GGGAACAACCTTCCCCAAGTCCCTTGGGAGCTCCAGG CTATCGCG GGCTGCCGG 15 CCGGCAGC C CGCGATAG 16 Adenosine DeaminaseGCTCCCAAGGGACTTGGGGAAGGTTGTTCCCAACCCCTTTCT 17 DeficiencyTCCCTTCCCAGGGGCTGC C GGGAGGCTATCAAAAGGATCGC ARG76TRPCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCGTGG CGG to TGGCCACGCCCTCTTTGGCCTTCATCTCTACAAACTCATAGGCGAT 18 CCTTTTGATAGCCTCCC GGCAGCCCCTGGGAAGGGAAGAAA GGGGTTGGGAACAACCTTCCCCAAGTCCCTTGGGAGC GGGGCTGC CGGGAGGCT 19 AGCCTCCC G GCAGCCCC 20 Adenosine DeaminaseTTGGGGAAGGTTGTTCCCAACCCCTTTCTTCCCTTCCCAGGG 21 DeficiencyGCTGCCGGGAGGCTATCA A AAGGATCGCCTATGAGTTTGTAG LYS80ARGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAGGT AAA to AGAACCTCCACATACACCACGCCCTCTTTGGCCTTCATCTCTACAA 22 ACTCATAGGCGATCCTT TTGATAGCCTCCCGGCAGCCCCTGG GAAGGGAAGAAAGGGGTTGGGAACAACCTTCCCCAA GGCTATCA AAAGGATCG 23 CGATCCTT T TGATAGCC 24 Adenosine deaminaseGTTGTTCCCAACCCCTTTCTTCCCTTCCCAGGGGCTGCCGGG 25 deficiencyAGGCTATCAAAAGGATCG C CTATGAGTTTGTAGAGATGAAGG ALA83ASPCCAAAGAGGGCGTGGTGTATGTGGAGGTGCGGTACAG GCC to GACCTGTACCGCACCTCCACATACACCACGCCCTCTTTGGCCTTC 26 ATCTCTACAAACTCATAG GCGATCCTTTTGATAGCCTCCCGGC AGCCCCTGGGAAGGGAAGAAAGGGGTTGGGAACAAC AAGGATCG CCTATGAGT 27 ACTCATAG G CGATCCTT 28 Adenosine deaminaseAGGCTATCAAAAGGATCGCCTATGAGTTTGTAGAGATGAAGG 29 deficiencyCCAAAGAGGGCGTGGTGT A TGTGGAGGTGCGGTACAGTCCG TYR97CYSCACCTGCTGGCCAACTCCAAAGTGGAGCCAATCCCCTG TAT to TGTCAGGGGATTGGCTCCACTTTGGAGTTGGCCAGCAGGTGCGG 30 ACTGTACCGCACCTCCACA TACACCACGCCCTCTTTGGCCTT CATCTCTACAAACTCATAGGCGATCCTTTTGATAGCCT CGTGGTGT ATGTGGAGG 31 CCTCCACA T ACACCACG 32 Adenosine deaminaseGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCG 33 deficiencyTGGTGTATGTGGAGGTGC G GTACAGTCCGCACCTGCTGGCC ARG101GLNAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTGA CGG to CAGTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCC 34 AGCAGGTGCGGACTGTAC CGCACCTCCACATACACCACGCC CTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCC GGAGGTGC GGTACAGTC 35 GACTGTAC C GCACCTCC 36 Adenosine deaminaseGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCG 37 deficiencyTGGTGTATGTGGAGGTGC G GTACAGTCCGCACCTGCTGGCC ARG101LEUAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTGA CGG to CTGTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCC 38 AGCAGGTGCGGACTGTAC CGCACCTCCACATACACCACGCC CTCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCC GGAGGTGC GGTACAGTC 39 GACTGTAC C GCACCTCC 40 Adenosine deaminaseAGGATCGCCTATGAGTTTGTAGAGATGAAGGCCAAAGAGGGC 41 deficiencyGTGGTGTATGTGGAGGTG C GGTACAGTCCGCACCTGCTGGC ARG101TRPCAACTCCAAAGTGGAGCCAATCCCCTGGAACCAGGCTG CGG to TGGCAGCCTGGTTCCAGGGGATTGGCTCCACTTTGGAGTTGGCCA 42 GCAGGTGCGGACTGTACC GCACCTCCACATACACCACGCCC TCTTTGGCCTTCATCTCTACAAACTCATAGGCGATCCT TGGAGGTG CGGTACAGT 43 ACTGTACC G CACCTCCA 44 Adenosine deaminaseATGAGTTTGTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATG 45 deficiencyTGGAGGTGCGGTACAGTC C GCACCTGCTGGCCAACTCCAAA PRO104LEUGTGGAGCCAATCCCCTGGAACCAGGCTGAGTGAGTGAT CCG to CTGATCACTCACTCAGCCTGGTTCCAGGGGATTGGCTCCACTTTG 46 GAGTTGGCCAGCAGGTGC GGACTGTACCGCACCTCCACATA CACCACGCCCTCTTTGGCCTTCATCTCTACAAACTCAT GTACAGTC CGCACCTGC 47 GCAGGTGC G GACTGTAC 48 Adenosine deaminaseTTTGTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAG 49 deficiencyGTGCGGTACAGTCCGCAC C TGCTGGCCAACTCCAAAGTGGA LEU106VALGCCAATCCCCTGGAACCAGGCTGAGTGAGTGATGGGCC CTG to GTGGGCCCATCACTCACTCAGCCTGGTTCCAGGGGATTGGCTCCA 50 CTTTGGAGTTGGCCAGCA GGTGCGGACTGTACCGCACCTCC ACATACACCACGCCCTCTTTGGCCTTCATCTCTACAAA GTCCGCAC CTGCTGGCC 51 GGCCAGCA G GTGCGGAC 52 Adenosine deaminaseTAGAGATGAAGGCCAAAGAGGGCGTGGTGTATGTGGAGGTG 53 deficiencyCGGTACAGTCCGCACCTGC T GGCCAACTCCAAAGTGGAGCC LEU107PROAATCCCCTGGAACCAGGCTGAGTGAGTGATGGGCCTGGA CTG to CCGTCCAGGCCCATCACTCACTCAGCCTGGTTCCAGGGGATTGGC 54 TCCACTTTGGAGTTGGCC AGCAGGTGCGGACTGTACCGCAC CTCCACATACACCACGCCCTCTTTGGCCTTCATCTCTA GCACCTGC TGGCCAACT 55 AGTTGGCC A GCAGGTGC 56 Adenosine deaminaseGCCTTCCTTTTGCCTCAGGCCCATCCCTACTCCTCTCCTCAC 57 deficiencyACAGAGGGGACCTCACCC C AGACGAGGTGGTGGCCCTAGTG PRO126GLNGGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGT CCA to CAAACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCAC 58 TAGGGCCACCACCTCGTCT GGGGTGAGGTCCCCTCTGTGTG AGGAGAGGAGTAGGGATGGGCCTGAGGCAAAAGGAAGGC CCTCACCC CAGACGAGG 59 CCTCGTCT G GGGTGAGG 60 Adenosine deaminaseTTTGCCTCAGGCCCATCCCTACTCCTCTCCTCACACAGAGGG 61 deficiencyGACCTCACCCCAGACGAG G TGGTGGCCCTAGTGGGCCAGGG VAL129METCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC GTG to ATGGGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCCC 62 TGGCCCACTAGGGCCACCA CCTCGTCTGGGGTGAGGTCCCC TCTGTGTGAGGAGAGGAGTAGGGATGGGCCTGAGGCAAA CAGACGAG GTGGTGGCC 63 GGCCACCA C CTCGTCTG 64 Adenosine deaminaseACAGAGGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTG 65 deficiencyGGCCAGGGCCTGCAGGAGG G GGAGCGAGACTTCGGGGTCA GLY140GLUAGGCCCGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAG GGG to GAGCTGGGCTGGTGGCGCATGCAGCACAGGATGGACCGGGCCTT 66 GACCCCGAAGTCTCGCTCC CCCTCCTGCAGGCCCTGGCCCA CTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCCTCTGT GCAGGAGG GGGAGCGAG 67 CTCGCTCC C CCTCCTGC 68 Adenosine deaminaseGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCAG 69 deficiencyGGCCTGCAGGAGGGGGAGC G AGACTTCGGGGTCAAGGCCC ARG142GLNGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGTA CGA to CAATACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACCG 70 GGCCTTGACCCCGAAGTCT CGCTCCCCCTCCTGCAGGCCCT GGCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCC GGGGGAGC GAGACTTCG 71 CGAAGTCT C GCTCCCCC 72 Adenosine deaminaseGGGGACCTCACCCCAGACGAGGTGGTGGCCCTAGTGGGCCA 73 deficiencyGGGCCTGCAGGAGGGGGAG C GAGACTTCGGGGTCAAGGCC ARG142TERMCGGTCCATCCTGTGCTGCATGCGCCACCAGCCCAGTGAGT CGA to TGAACTCACTGGGCTGGTGGCGCATGCAGCACAGGATGGACCGG 74 GCCTTGACCCCGAAGTCTC GCTCCCCCTCCTGCAGGCCCTG GCCCACTAGGGCCACCACCTCGTCTGGGGTGAGGTCCCC AGGGGGAG CGAGACTTC 75 GAAGTCTC G CTCCCCCT 76 Adenosine deaminaseTGGTGGCCCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGCG 77 deficiencyAGACTTCGGGGTCAAGGCCC G GTCCATCCTGTGCTGCATGC ARG149GLNGCCACCAGCCCAGTGAGTAGGATCACCGCCCTGCCCAGGG CGG to CAGCCCTGGGCAGGGCGGTGATCCTACTCACTGGGCTGGTGGCG 78 CATGCAGCACAGGATGGAC CGGGCCTTGACCCCGAAGTCTC GCTCCCCCTCCTGCAGGCCCTGGCCCACTAGGGCCACCA CAAGGCCC GGTCCATCC 79 GGATGGAC C GGGCCTTG 80 Adenosine deaminaseGTGGTGGCCCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGC 81 deficiencyGAGACTTCGGGGTCAAGGCC C GGTCCATCCTGTGCTGCATG ARG149TRPCGCCACCAGCCCAGTGAGTAGGATCACCGCCCTGCCCAGG CGG to TGGCCTGGGCAGGGCGGTGATCCTACTCACTGGGCTGGTGGCGC 82 ATGCAGCACAGGATGGACC GGGCCTTGACCCCGAAGTCTCG CTCCCCCTCCTGCAGGCCCTGGCCCACTAGGGCCACCAC TCAAGGCC CGGTCCATC 83 GATGGACC G GGCCTTGA 84 Adenosine deaminaseCTAGTGGGCCAGGGCCTGCAGGAGGGGGAGCGAGACTTCG 85 deficiencyGGGTCAAGGCCCGGTCCATC C TGTGCTGCATGCGCCACCAG LEU152METCCCAGTGAGTAGGATCACCGCCCTGCCCAGGGCCGCCCGT CTG to ATGACGGGCGGCCCTGGGCAGGGCGGTGATCCTACTCACTGGG 86 CTGGTGGCGCATGCAGCACA GGATGGACCGGGCCTTGACCC CGAAGTCTCGCTCCCCCTCCTGCAGGCCCTGGCCCACTAG GGTCCATC CTGTGCTGC 87 GCAGCACA G GATGGACC 88 Adenosine deaminaseGGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCC 89 deficiencyGGTCCATCCTGTGCTGCATG C GCCACCAGCCCAGTGAGTAG ARG156CYSGATCACCGCCCTGCCCAGGGCCGCCCGTCTCACCCTGGCC CGC to TGCGGCCAGGGTGAGACGGGCGGCCCTGGGCAGGGCGGTGATC 90 CTACTCACTGGGCTGGTGGC GCATGCAGCACAGGATGGACC GGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGCC GCTGCATG CGCCACCAG 91 CTGGTGGC G CATGCAGC 92 Adenosine deaminaseGCCTGCAGGAGGGGGAGCGAGACTTCGGGGTCAAGGCCCG 93 deficiencyGTCCATCCTGTGCTGCATGC G CCACCAGCCCAGTGAGTAGG ARG156HISATCACCGCCCTGCCCAGGGCCGCCCGTCTCACCCTGGCCC CGC to CACGGGCCAGGGTGAGACGGGCGGCCCTGGGCAGGGCGGTGAT 94 CCTACTCACTGGGCTGGTGG CGCATGCAGCACAGGATGGAC CGGGCCTTGACCCCGAAGTCTCGCTCCCCCTCCTGCAGGC CTGCATGC GCCACCAGC 95 GCTGGTGG C GCATGCAG 96 Adenosine deaminaseCTGCCCACAGACTGGTCCCCCAAGGTGGTGGAGCTGTGTAA 97 deficiencyGAAGTACCAGCAGCAGACC G TGGTAGCCATTGACCTGGCTG VAL177METGAGATGAGACCATCCCAGGAAGCAGCCTCTTGCCTGGAC GTG to ATGGTCCAGGCAAGAGGCTGCTTCCTGGGATGGTCTCATCTCCAG 98 CCAGGTCAATGGCTACCA CGGTCTGCTGCTGGTACTTCTTAC ACAGCTCCACCACCTTGGGGGACCAGTCTGTGGGCAG AGCAGACC GTGGTAGCC 99 GGCTACCA C GGTCTGCT 100 Adenosine deaminaseCAGACTGGTCCCCCAAGGTGGTGGAGCTGTGTAAGAAGTAC 101 deficiencyCAGCAGCAGACCGTGGTAG C CATTGACCTGGCTGGAGATGA ALA179ASPGACCATCCCAGGAAGCAGCCTCTTGCCTGGACATGTCCA GCC to GACTGGACATGTCCAGGCAAGAGGCTGCTTCCTGGGATGGTCTCA 102 TCTCCAGCCAGGTCAATG GCTACCACGGTCTGCTGCTGGTAC TTCTTACACAGCTCCACCACCTTGGGGGACCAGTCTG CGTGGTAG CCATTGACC 103 GGTCAATG G CTACCACG 104 Adenosine deaminaseCCATTGACCTGGCTGGAGATGAGACCATCCCAGGAAGCAGC 105 deficiencyCTCTTGCCTGGACATGTCC A GGCCTACCAGGTGGGTCCTGT GLN199PROGAGAAGGAATGGAGAGGCTGGCCCTGGGTGAGCTTGTCT CAG to CCGAGACAAGCTCACCCAGGGCCAGCCTCTCCATTCCTTCTCACA 106 GGACCCACCTGGTAGGCC TGGACATGTCCAGGCAAGAGGCT GCTTCCTGGGATGGTCTCATCTCCAGCCAGGTCAATGG ACATGTCC AGGCCTACC 107 GGTAGGCC T GGACATGT 108 Adenosine deaminaseGCTAGGGCACCCATGACCTGGCTCTCCCCCTTCCAGGAGGC 109 deficiencyTGTGAAGAGCGGCATTCAC C GTACTGTCCACGCCGGGGAGG ARG211CYSTGGGCTCGGCCGAAGTAGTAAAAGAGGTGAGGGCCTGGG CGT to TGTCCCAGGCCCTCACCTCTTTTACTACTTCGGCCGAGCCCACCT 110 CCCCGGCGTGGACAGTAC GGTGAATGCCGCTCTTCACAGCC TCCTGGAAGGGGGAGAGCCAGGTCATGGGTGCCCTAGC GCATTCAC CGTACTGTC 111 GACAGTAC G GTGAATGC 112 Adenosine deaminaseCTAGGGCACCCATGACCTGGCTCTCCCCCTTCCAGGAGGCT 113 deficiencyGTGAAGAGCGGCATTCACC G TACTGTCCACGCCGGGGAGGT ARG211HISGGGCTCGGCCGAAGTAGTAAAAGAGGTGAGGGCCTGGGC CGT to CATGCCCAGGCCCTCACCTCTTTTACTACTTCGGCCGAGCCCACC 114 TCCCCGGCGTGGACAGTA CGGTGAATGCCGCTCTTCACAGC CTCCTGGAAGGGGGAGAGCCAGGTCATGGGTGCCCTAG CATTCACC GTACTGTCC 115 GGACAGTA C GGTGAATG 116 Adenosine deaminaseATGACCTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGG 117 deficiencyCATTCACCGTACTGTCCAC G CCGGGGAGGTGGGCTCGGCCG ALA215THRAAGTAGTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGG GCC to ACCCCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTACTTCGG 118 CCGAGCCCACCTCCCCGG CGTGGACAGTACGGTGAATGCCG CTCTTCACAGCCTCCTGGAAGGGGGAGAGCCAGGTCAT CTGTCCAC GCCGGGGAG 119 CTCCCCGG C GTGGACAG 120 Adenosine deaminaseACCTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGGCAT 121 deficiencyTCACCGTACTGTCCACGCC G GGGAGGTGGGCTCGGCCGAAG GLY216ARGTAGTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGGTCC GGG to AGGGGACCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTACTT 122 CGGCCGAGCCCACCTCCC CGGCGTGGACAGTACGGTGAATG CCGCTCTTCACAGCCTCCTGGAAGGGGGAGAGCCAGGT TCCACGCC GGGGAGGTG 123 CACCTCCC C GGCGTGGA 124 Adenosine deaminaseTGGCTCTCCCCCTTCCAGGAGGCTGTGAAGAGCGGCATTCA 125 deficiencyCCGTACTGTCCACGCCGGG G AGGTGGGCTCGGCCGAAGTAG GLU217LYSTAAAAGAGGTGAGGGCCTGGGCTGGCCATGGGGTCCCTC GAG to AAGGAGGGACCCCATGGCCAGCCCAGGCCCTCACCTCTTTTACTA 126 CTTCGGCCGAGCCCACCT CCCCGGCGTGGACAGTACGGTGA ATGCCGCTCTTCACAGCCTCCTGGAAGGGGGAGAGCCA ACGCCGGG GAGGTGGGC 127 GCCCACCT C CCCGGCGT 128 Adenosine deaminaseCTGCCTCCTCCCATACTTGGCTCTATTCTGCTTCTCTACAGGC 129 deficiencyTGTGGACATACTCAAGA C AGAGCGGCTGGGACACGGCTACC THR233ILEACACCCTGGAAGACCAGGCCCTTTATAACAGGCTGCG ACA to ATACGCAGCCTGTTATAAAGGGCCTGGTCTTCCAGGGTGTGGTAG 130 CCGTGTCCCAGCCGCTCT GTCTTGAGTATGTCCACAGCCTGT AGAGAAGCAGAATAGAGCCAAGTATGGGAGGAGGCAG ACTCAAGA CAGAGCGGC 131 GCCGCTCT G TCTTGAGT 132 Adenosine deaminaseCAGAGCGGCTGGGACACGGCTACCACACCCTGGAAGACCAG 133 deficiencyGCCCTTTATAACAGGCTGC G GCAGGAAAACATGCACTTCGAG ARG253PROGTAAGCGGGCCAGGGAGTGGGGAGGAACCATCCCCGGC CGG to CCGGCCGGGGATGGTTCCTCCCCACTCCCTGGCCCGCTTACCTC 134 GAAGTGCATGTTTTCCTGC CGCAGCCTGTTATAAAGGGCCTG GTCTTCCAGGGTGTGGTAGCCGTGTCCCAGCCGCTCTG CAGGCTGC GGCAGGAAA 135 TTTCCTGC C GCAGCCTG 136 Adenosine deaminaseGAGCGGCTGGGACACGGCTACCACACCCTGGAAGACCAGGC 137 deficiencyCCTTTATAACAGGCTGCGG C AGGAAAACATGCACTTCGAGGT GLN254TERMAAGCGGGCCAGGGAGTGGGGAGGAACCATCCCCGGCTG CAG to TAGCAGCCGGGGATGGTTCCTCCCCACTCCCTGGCCCGCTTACC 138 TCGAAGTGCATGTTTTCCT GCCGCAGCCTGTTATAAAGGGCC TGGTCTTCCAGGGTGTGGTAGCCGTGTCCCAGCCGCTC GGCTGCGG CAGGAAAAC 139 GTTTTCCT G CCGCAGCC 140 Adenosine deaminaseCCACACACCTGCTCTTCCAGATCTGCCCCTGGTCCAGCTACC 141 deficiencyTCACTGGTGCCTGGAAGC C GGACACGGAGCATGCAGTCATT PRO274LEUCGGTGAGCTCTGTTCCCCTGGGCCTGTTCAATTTTGTT CCG to CTGAACAAAATTGAACAGGCCCAGGGGAACAGAGCTCACCGAATG 142 ACTGCATGCTCCGTGTCC GGCTTCCAGGCACCAGTGAGGTA GCTGGACCAGGGGCAGATCTGGAAGAGCAGGTGTGTGG CTGGAAGC CGGACACGG 143 CCGTGTCC G GCTTCCAG 144 Adenosine deaminaseGGAGGCTGATTCTCTCCTCCTCCCTCTTCTGCAGGCTCAAAA 145 deficiencyATGACCAGGCTAACTACT C GCTCAACACAGATGACCCGCTCA SER291LEUTCTTCAAGTCCACCCTGGACACTGATTACCAGATGAC TCG to TTGGTCATCTGGTAATCAGTGTCCAGGGTGGACTTGAAGATGAGC 146 GGGTCATCTGTGTTGAGC GAGTAGTTAGCCTGGTCATTTTTGA GCCTGCAGAAGAGGGAGGAGGAGAGAATCAGCCTCC TAACTACT CGCTCAACA 147 TGTTGAGC G AGTAGTTA 148 Adenosine deaminaseCCTCCCTCTTCTGCAGGCTCAAAAATGACCAGGCTAACTACT 149 deficiencyCGCTCAACACAGATGACC C GCTCATCTTCAAGTCCACCCTGG PRO297GLNACACTGATTACCAGATGACCAAACGGGACATGGGCTT CCG to CAGAAGCCCATGTCCCGTTTGGTCATCTGGTAATCAGTGTCCAGG 150 GTGGACTTGAAGATGAGC GGGTCATCTGTGTTGAGCGAGTAG TTAGCCTGGTCATTTTTGAGCCTGCAGAAGAGGGAGG AGATGACC CGCTCATCT 151 AGATGAGC G GGTCATCT 152 Adenosine deaminaseAAAATGACCAGGCTAACTACTCGCTCAACACAGATGACCCGC 153 deficiencyTCATCTTCAAGTCCACCC T GGACACTGATTACCAGATGACCAA LEU304ARGACGGGACATGGGCTTTACTGAAGAGGAGTTTAAAAG CTG to CGGCTTTTAAACTCCTCTTCAGTAAAGCCCATGTCCCGTTTGGTCA 154 TCTGGTAATCAGTGTCC AGGGTGGACTTGAAGATGAGCGGGT CATCTGTGTTGAGCGAGTAGTTAGCCTGGTCATTTT GTCCACCC TGGACACTG 155 CAGTGTCC A GGGTGGAC 156 Adenosine deaminaseGCCTTCTTTGTTCTCTGGTTCCATGTTGTCTGCCATTCTGGCC 157 deficiencyTTTCCAGAACATCAATG C GGCCAAATCTAGTTTCCTCCCAGAA ALA329VALGATGAAAAGAGGGAGCTTCTCGACCTGCTCTATAA C-to-T at base 1081TTATAGAGCAGGTCGAGAAGCTCCCTCTTTTCATCTTCTGGGA 158 GGAAACTAGATTTGGCC GCATTGATGTTCTGGAAAGGCCAGA ATGGCAGACAACATGGAACCAGAGAACAAAGAAGGC CATCAATG CGGCCAAAT 159 ATTTGGCC G CATTGATG 160

EXAMPLE 5 P53 Mutations

[0110] The p53 gene codes for a protein that acts as a transcriptionfactor and serves as a key regulator of the cell cycle. Mutation in thisgene is probably the most significant genetic change characterizing thetransformation of cells from normalcy to malignancy.

[0111] Inactivation of p53 by mutation disrupts the cell cycle which, inturn, sets the stage for tumor formation. Mutations in the p53 gene areamong the most commonly diagnosed genetic disorders, occuring in as manyas 50% of cancer patients. For some types of cancer, most notably of thebreast, lung and colon, p53 mutations are the predominant geneticalternations found thus far. These mutations are associated with genomicinstability and thus an increased susceptibility to cancer. Some p53lesions result in malignancies that are resistant to the most widelyused therapeutic regimens and therefore demand more aggressivetreatment.

[0112] That p53 is associated with different malignant tumors isillustrated in the Li-Fraumeni autosomal dominant hereditary disordercharacterized by familial multiple tumors due to mutation in the p53gene. Affected individuals can develop one or more tumors, including:brain (12%); soft-tissue sarcoma (12%); breast cancer (25%); adrenaltumors (1%); bone cancer (osteosarcoma) (6%); cancer of the lung,prostate, pancreas, and colon as well as lymphoma and melanoma can alsooccur.

[0113] Certain of the most frequenty mutated codons are codons 175, 248and 273, however a variety of oligonucleotides are described below inthe attached table. TABLE 11 p53 Mutations and Genome-Correcting OligosClinical Phenotype & SEQ ID Mutation Correcting Oligos NO: In 2 familieswith GACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCT 161 Li-FraumeniGCATGGGCGGCATGAAC C GGAGGCCCATCCTCACCATCATC syndrome, there was aACACTGGAAGACTCCAGGTCAGGAGCCACTTGCCACC C-to-T mutation at the firstnucleotide of GGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGA 162 codon 248which TGGTGAGGATGGGCCTCC G GTTCATGCCGCCCATGCAGGAA changed arginine toCTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGTC tryptophan. GCATGAAC C GGAGGCCC163 GGGCCTCC G GTTCATGC 164 In a family with theTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCCAT 165 Li-FraumeniCCTCACCATCATCACACTG G AAGACTCCAGGTCAGGAGCCAC syndrome, a G-to-ATTGCCACCCTGCACACTGGCCTGCTGTGCCCCAGCCTC mutation at the first nucleotideof codon GAGGCTGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGT 166 258 resulting inthe GGCTCCTGACCTGGAGTCTT C CAGTGTGATGATGGTGAGGAT substitution of lysineGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACA for glutamic acid. TCACACTG GAAGACTCC 167 GGAGTCTT C CAGTGTGA 168 In a family with theGTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTA 169 Li-FraumeniACAGTTCCTGCATGGGC G GCATGAACCGGAGGCCCATCCTC syndrome, a G-to-TACCATCATCACACTGGAAGACTCCAGGTCAGGAGCCA mutation at the first nucleotideof codon 245 resulting in the substitution of cysteine for glycine. Agly245-to-ser, TGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGGA 170GGC-to-AGC, TGGGCCTCCGGTTCATGC C GCCCATGCAGGAACTGTTACACA mutation wasfound in TGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCAAC a patient in whomosteosarcoma was GCATGGGC G GCATGAAC 171 diagnosed at the age of 18years. GTTCATGC C GCCCATGC 172 In a family with theTCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGGCA 173 Li-FraumeniTGAACCGGAGGCCCATCC T CACCATCATCACACTGGAAGACT syndrome, a germlineCCAGGTCAGGAGCCACTTGCCACCCTGCACACTGGCC mutation at codon 252: a T-to-Cchange at the GGCCAGTGTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTC 174 secondposition TTCCAGTGTGATGATGGTG A GGATGGGCCTCCGGTTCATGCC resulted insubstitution GCCCATGCAGGAACTGTTACACATGTAGTTGTAGTGGA of proline forleucine. GCCCATCC T CACCATCA 175 TGATGGTG A GGATGGGC 176 Researchersanalyzed TACCACCATCCACTACAACTACATGTGTAACAGTTCCTGCATG 177 for mutationsin p53 GGCGGCATGAACCGGAG G CCCATCCTCACCATCATCACACT hepatocellularGGAAGACTCCAGGTCAGGAGCCACTTGCCACCCTGCA carcinomas from patients inQidong, an area of high incidenceTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTG 178 in China, in which bothTGATGATGGTGAGGATGGG C CTCCGGTTCATGCCGCCCATG hepatitis B virus andCAGGAACTGTTACACATGTAGTTGTAGTGGATGGTGGTA aflatoxin B1 are risk factors.Eight of 16 tumors had a point AACCGGAG G CCCATCCT 179 mutation at thethird base position of codon 249. The G-to-T mutation at codon 249AGGATGGG C CTCCGGTT 180 led to a change from arginine to serine (AGG toAGT). In cases of CTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTGATTCCACA 181hepatocellular CCCCCGCCCGGCACCCGC G TCCGCGCCATGGCCATCTACAA carcinoma insouthern GCAGTCACAGCACATGACGGAGGTTGTGAGGCGCTGCC Africa, a G-to-Tsubstitution in codon GGCAGCGCCTCACAACCTCCGTCATGTGCTGTGACTGCTTGT 182 157resulting in a AGATGGCCATGGCGCGGA C GCGGGTGCCGGGCGGGGGTGT change fromvaline to GGAATCAACCCACAGCTGCACAGGGCAGGTCTTGGCCAG phenylalanine.GCACCCGC G TCCGCGCC 183 GGCGCGGA C GCGGGTGC 184 In a family withTTGGCTCTGACTGTACCACCATCCACTACAACTACATGTGTAA 185 Li-Fraumeni in whichCAGTTCCTGCATGGGCG G CATGAACCGGAGGCCCATCCTCA noncancerous skinCCATCATCACACTGGAAGACTCCAGGTCAGGAGCCAC fibroblasts from affectedindividuals GTGGCTCCTGACCTGGAGTCTTCCAGTGTGATGATGGTGAGG 186 showed anunusual ATGGGCCTCCGGTTCATG C CGCCCATGCAGGAACTGTTACAC radiation-resistantATGTAGTTGTAGTGGATGGTGGTACAGTCAGAGCCAA phenotype, a point mutation incodon 245 CATGGGCG G CATGAACC 187 of the P53 gene. A change from GGC toCAC predicted GGTTCATG C CGCCCATG 188 substitution of aspartic acid forglycine. In 2 of 8 families withACTGTACCACCATCCACTACAACTACATGTGTAACAGTTCCTG 189 Li-FraumeniCATGGGCGGCATGAACC G GAGGCCCATCCTCACCATCATCA syndrome, a mutationCACTGGAAGACTCCAGGTCAGGAGCCACTTGCCACCC in codon 248: a CGG-to-CAG changeGGGTGGCAAGTGGCTCCTGACCTGGAGTCTTCCAGTGTGAT 190 resulting in substitutionGATGGTGAGGATGGGCCTC C GGTTCATGCCGCCCATGCAGG of glutamine forAACTGTTACACATGTAGTTGTAGTGGATGGTGGTACAGT arginine. CATGAACC G GAGGCCCA191 TGGGCCTC C GGTTCATG 192 In 9 members of anCCCTGACTTTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTC 193 extended family withCCCTGCCCTCAACAAGA T GTTTTGCCAACTGGCCAAGACCTG Li-FraumeniCCCTGTGCAGCTGTGGGTTGATTCCACACCCCCGCC syndrome, a germline mutation atcodon 133 GGCGGGGGTGTGGAATCAACCCACAGCTGCACAGGGCAGGT 194 (ATG-to-ACG),CTTGGCCAGTTGGCAAAAC A TCTTGTTGAGGGCAGGGGAGTA resulted in theCTGTAGGAAGAGGAAGGAGACAGAGTTGAAAGTCAGGG substitution of threonine forCAACAAGA T GTTTTGCC 195 methionine (M133T), and completely cosegregatedwith the GGCAAAAC A TCTTGTTG 196 cancer syndrome. In 1 pedigreeTCTTGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGG 197 consistent with theGACGGAACAGCTTTGAG G TGCGTGTTTGTGCCTGTCCTGGGA Li-FraumeniGAGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGA syndrome, a germline G-to-Ttransversion at TCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTCCCAG 198 codon 272(valine to GACAGGCACAAACACGCA C CTCAAAGCTGTTCCGTCCCAGTA leucine) wasfound. GATTACCACTACTCAGGATAGGAAAAGAGAAGCAAGA GCTTTGAG G TGCGTGTT 199AACACGCA C CTCAAAGC 200 A ser241-to-pheTTATCTCCTAGGTTGGCTCTGACTGTACCACCATCCACTACAA 201 mutation due to aCTACATGTGTAACAGTT C CTGCATGGGCGGCATGAACCGGAG TCC-to-TTC changeGCCCATCCTCACCATCATCACACTGGAAGACTCCAG was found in a patient withhepatoblastoma CTGGAGTCTTCCAGTGTGATGATGGTGAGGATGGGCCTCCG 202 andmultiple foci of CTTCATGCCGCCCATGCAG G AACTGTTACACATGTAGTTGTAosteosarcoma GTGGATGGTGGTACAGTCAGAGCCAACCTAGGAGATAA TAACAGTT C CTGCATGG203 CCATGCAG G AACTGTTA 204 An AAG-to-TAGCAGAAAACCTACCAGGGCAGCTACGGTTTCCGTCTGGGCTTC 205 change of codon 120,TTGCATTCTGGGACAGCC A AGTCTGTGACTTGCACGGTCAGT resulting in conversionTGCCCTGAGGGGCTGGCTTCCATGAGACTTCAATGCC from lysine to a stop codon, wasfound in a GGCATTGAAGTCTCATGGAAGCCAGCCCCTCAGGGCAACTG 206 patient withACCGTGCAAGTCACAGACT T GGCTGTCCCAGAATGCAAGAAG osteosarcoma andCCCAGACGGAAACCGTAGCTGCCCTGGTAGGTTTTCTG adenocarcinoma of the lung at age18 and GGACAGCC A AGTCTGTG 207 brain tumor (glioma) at the age of 27.CACAGACT T GGCTGTCC 208 A CGG-to-TGGGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTGTTTGT 209 change at codon 282,GCCTGTCCTGGGAGAGAC C GGCGCACAGAGGAAGAGAATCT resulting in theCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCCCCAG substitution of tryptophan forargi- CTGGGGGCAGCTCGTGGTGAGGCTCCCCTTTCTTGCGGAGA 210 nine, was found in aTTCTCTTCCTCTGTGCGCC G GTCTCTCCCAGGACAGGCACAA patient who developedACACGCACCTCAAAGCTGTTCCGTCCCAGTAGATTACC osteosarcoma at the age of 10years. GGAGAGAC C GGCGCACA 211 TGTGCGCC G GTCTCTCC 212 In 5 of 6anaplastic GCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGACG 213 carcinomas ofthe GAACAGCTTTGAGGTGC G TGTTTGTGCCTGTCCTGGGAGAGA thyroid and in anCCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGG anaplastic carcinoma thyroid cellline ARO, a CCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTC 214 CGT-to-CATmutation CCAGGACAGGCACAAACA C GCACCTCAAAGCTGTTCCGTCCC convertedAGTAGATTACCACTACTCAGGATAGGAAAAGAGAAGC arginine-273 to histidine.TGAGGTGC G TGTTTGTG 215 CACAAACA C GCACCTCA 216 A germlineTCCTAGCACTGCCCAACAACACCAGCTCCTCTCCCCAGCCAA 217 GGA-to-GTA mutationAGAAGAAACCACTGGATG G AGAATATTTCACCCTTCAGGTACT resulting in a changeAAGTCTTGGGACCTCTTATCAAGTGGAAAGTTTCCA of glycine-325 to valineTGGAAACTTTCCACTTGATAAGAGGTCCCAAGACTTAGTACCT 218 was found in a patientGAAGGGTGAAATATTCT C CATCCAGTGGTTTCTTCTTTGGCTG who had non-HodgkinGGGAGAGGAGCTGGTGTTGTTGGGCAGTGCTAGGA lymphoma diagnosed at age 17 andcolon ACTGGATG G AGAATATT 219 carcinoma at age 26. AATATTCT C CATCCAGT220 CGC-CCC AATGGTTCACTGAAGACCCAGGTCCAGATGAAGCTCCCAGAA 221 Arg-72 to ProTGCCAGAGGCTGCTCCCC G CGTGGCCCCTGCACCAGCAGCT association with LungCCTACACCGGCGGCCCCTGCACCAGCCCCCTCCTGGCC cancerGGCCAGGAGGGGGCTGGTGCAGGGGCCGCCGGTGTAGGAG 222 CTGCTGGTGCAGGGGCCACG CGGGGAGCAGCCTCTGGCATT CTGGGAGCTTCATCTGGACCTGGGTCTTCAGTGAACCATT TGCTCCCC GCGTGGCCC 223 GGGCCACG C GGGGAGCA 224 CCG-CTGAAGCTCCCAGAATGCCAGAGGCTGCTCCCCGCGTGGCCCCT 225 Pro-82 to LeuGCACCAGCAGCTCCTACAC C GGCGGCCCCTGCACCAGCCCC Breast cancerCTCCTGGCCCCTGTCATCTTCTGTCCCTTCCCAGAAAACGTTTTCTGGGAAGGGACAGAAGATGACAGGGGCCAGGAGGG 226 GGCTGGTGCAGGGGCCGCC GGTGTAGGAGCTGCTGGTGCA GGGGCCACGCGGGGAGCAGCCTCTGGCATTCTGGGAGCTT TCCTACAC CGGCGGCCC 227 GGGCCGCC G GTGTAGGA 228 cCAA-TAATTCAACTCTGTCTCCTTCCTCTTCCTACAGTACTCCCCTGCCC 229 Gln-136 to TermTCAACAAGATGTTTTGC C AACTGGCCAAGACCTGCCCTGTGC Li-Fraumeni syndromeAGCTGTGGGTTGATTCCACACCCCCGCCCGGCACCCGGGTGCCGGGCGGGGGTGTGGAATCAACCCACAGCTGCACA 230 GGGCAGGTCTTGGCCAGTT GGCAAAACATCTTGTTGAGGGCA GGGGAGTACTGTAGGAAGAGGAAGGAGACAGAGTTGAA TGTTTTGC CAACTGGCC 231 GGCCAGTT G GCAAAACA 232 TGC-TACTCCTCTTCCTACAGTACTCCCCTGCCCTCAACAAGATGTTTTG 233 Cys-141 to TyrCCAACTGGCCAAGACCT G CCCTGTGCAGCTGTGGGTTGATTC Li-Fraumeni syndromeCACACCCCCGCCCGGCACCCGCGTCCGCGCCATGGCGCCATGGCGCGGACGCGGGTGCCGGGCGGGGGTGTGGAAT 234 CAACCCACAGCTGCACAGGG CAGGTCTTGGCCAGTTGGCAA AACATCTTGTTGAGGGCAGGGGAGTACTGTAGGAAGAGGA CAAGACCT GCCCTGTGC 235 GCACAGGG C AGGTCTTG 236 aCCC-TCCAACAAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAG 237 Pro-151 to SerCTGTGGGTTGATTCCACA C CCCCGCCCGGCACCCGCGTCCG Li-Fraumeni syndromeCGCCATGGCCATCTACAAGCAGTCACAGCACATGACGGCCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCGCGG 238 ACGCGGGTGCCGGGCGGGG GTGTGGAATCAACCCACAGCT GCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCTTGTT ATTCCACA CCCCCGCCC 239 GGGCGGGG G TGTGGAAT 240 CCG-CTGAGATGTTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGT 241 Pro-152 to LeuGGGTTGATTCCACACCCC C GCCCGGCACCCGCGTCCGCGCC AdrenocorticalATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGT carcinomaACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCATGGCG 242 CGGACGCGGGTGCCGGGC GGGGGTGTGGAATCAACCCACA GCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAAACATCT CACACCCC CGCCCGGCA 243 TGCCGGGC G GGGGTGTG 244 GGC-GTCTTTGCCAACTGGCCAAGACCTGCCCTGTGCAGCTGTGGGTTG 245 Gly-154 to ValATTCCACACCCCCGCCCG G CACCCGCGTCCGCGCCATGGCC GlioblastomaATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGCTCACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCC 246 ATGGCGCGGACGCGGGTG CCGGGCGGGGGTGTGGAATCAA CCCACAGCTGCACAGGGCAGGTCTTGGCCAGTTGGCAAA CCCGCCCG GCACCCGCG 247 CGCGGGTG C CGGGCGGG 248 CGC-CACCCCGCGTCCGCGCCATGGCCATCTACAAGCAGTCACAGCAC 249 Arg-175 to HisATGACGGAGGTTGTGAGGC G CTGCCCCCACCATGAGCGCTG Li-Fraumeni syndromeCTCAGATAGCGATGGTGAGCAGCTGGGGCTGGAGAGACGCGTCTCTCCAGCCCCAGCTGCTCACCATCGCTATCTGAGCAG 250 CGCTCATGGTGGGGGCAG CGCCTCACAACCTCCGTCATGTG CTGTGACTGCTTGTAGATGGCCATGGCGCGGACGCGGG TGTGAGGC GCTGCCCCC 251 GGGGGCAG C GCCTCACA 252 tGAG-AAGATGGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTG 253 Glu-180 to LysAGGCGCTGCCCCCACCAT G AGCGCTGCTCAGATAGCGATGG Li-Fraumeni syndromeTGAGCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTCACCAT 254 CGCTATCTGAGCAGCGCT CATGGTGGGGGCAGCGCCTCACA ACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGCCAT CCCACCAT GAGCGCTGC 255 GCAGCGCT C ATGGTGGG 256 gCGC-TGCGCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGG 257 Arg-181 to CysCGCTGCCCCCACCATGAG C GCTGCTCAGATAGCGATGGTGA Breast cancerGCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCCCATGGGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTCA 258 CCATCGCTATCTGAGCAGC GCTCATGGTGGGGGCAGCGCCT CACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGGC ACCATGAG CGCTGCTCA 259 TGAGCAGC G CTCATGGT 260 CGC-CACCCATCTACAAGCAGTCACAGCACATGACGGAGGTTGTGAGGC 261 Arg-81 to HisGCTGCCCCCACCATGAGC G CTGCTCAGATAGCGATGGTGAG Breast cancerCAGCTGGGGCTGGAGAGACGACAGGGCTGGTTGCCCAGCTGGGCAACCAGCCCTGTCGTCTCTCCAGCCCCAGCTGCTC 262 ACCATCGCTATCTGAGCAG CGCTCATGGTGGGGGCAGCGCC TCACAACCTCCGTCATGTGCTGTGACTGCTTGTAGATGG CCATGAGC GCTGCTCAG 263 CTGAGCAG C GCTCATGG 264 CAT-CGTCCAGGGTCCCCAGGCCTCTGATTCCTCACTGATTGCTCTTAG 265 His-193 to ArgGTCTGGCCCCTCCTCAGC A TCTTATCCGAGTGGAAGGAAATT Li-Fraumeni syndromeTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCGCGAAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAATTTC 266 CTTCCACTCGGATAAGA TGCTGAGGAGGGGCCAGACCTAAGA GCAATCAGTGAGGAATCAGAGGCCTGGGGACCCTGG TCCTCAGC ATCTTATCC 267 GGATAAGA T GCTGAGGA 268 cCGA-TGACCCAGGCCTCTGATTCCTCACTGATTGCTCTTAGGTCTGGCC 269 Arg-196 to TermCCTCCTCAGCATCTTATC C GAGTGGAAGGAAATTTGCGTGTG AdrenocorticalGAGTATTTGGATGACAGAAACACTTTTCGACATAGTG carcinomaCACTATGTCGAAAAGTGTTTCTGTCATCCAAATACTCCACACG 270 CAAATTTCCTTCCACTC GGATAAGATGCTGAGGAGGGGCCAG ACCTAAGAGCAATCAGTGAGGAATCAGAGGCCTGGG ATCTTATC CGAGTGGAA 271 TTCCACTC G GATAAGAT 272 cAGA-TGAGCCCCTCCTCAGCATCTTATCCGAGTGGAAGGAAATTTGCGT 273 Arg-209 to TermGTGGAGTATTTGGATGAC A GAAACACTTTTCGACATAGTGTG Li-Fraumeni syndromeGTGGTGCCCTATGAGCCGCCTGAGGTCTGGTTTGCAATTGCAAACCAGACCTCAGGCGGCTCATAGGGCACCACCACA 274 CTATGTCGAAAAGTGTTTC TGTCATCCAAATACTCCACACGCA AATTTCCTTCCACTCGGATAAGATGCTGAGGAGGGGC TGGATGAC AGAAACACT 275 AGTGTTTC T GTCATCCA 276 tCGA-TGACATCTTATCCGAGTGGAAGGAAATTTGCGTGTGGAGTATTTG 277 Arg-213 to TermGATGACAGAAACACTTTT C GACATAGTGTGGTGGTGCCCTAT Li-Fraumeni syndromeGAGCCGCCTGAGGTCTGGTTTGCAACTGGGGTCTCTGCAGAGACCCCAGTTGCAAACCAGACCTCAGGCGGCTCATAG 278 GGCACCACCACACTATGTC GAAAAGTGTTTCTGTCATCCAAAT ACTCCACACGCAAATTTCCTTCCACTCGGATAAGATG ACACTTTT CGACATAGT 279 ACTATGTC G AAAAGTGT 280 gCCC-TCCGGAAATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTC 281 Pro-219 to SerGACATAGTGTGGTGGTG C CCTATGAGCCGCCTGAGGTCTGG AdrenocorticalTTTGCAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGT carcinomaACCCTTAACCCCTCCTCCCAGAGACCCCAGTTGCAAACCAGA 282 CCTCAGGCGGCTCATAGG GCACCACCACACTATGTCGAAAAG TGTTTCTGTCATCCAAATACTCCACACGCAAATTTCC TGGTGGTG CCCTATGAG 283 CTCATAGG G CACCACCA 284 TAT-TGTATTTGCGTGTGGAGTATTTGGATGACAGAAACACTTTTCGACA 285 Tyr-220 to CysTAGTGTGGTGGTGCCCT A TGAGCCGCCTGAGGTCTGGTTTG Li-Fraumeni syndromeCAACTGGGGTCTCTGGGAGGAGGGGTTAAGGGTGGTTAACCACCCTTAACCCCTCCTCCCAGAGACCCCAGTTGCAAAC 286 CAGACCTCAGGCGGCTCA TAGGGCACCACCACACTATGTCG AAAAGTGTTTCTGTCATCCAAATACTCCACACGCAAAT GGTGCCCT ATGAGCCGC 287 GCGGCTCA T AGGGCACC 288 cTCT-ACTCACAGGTCTCCCCAAGGCGCACTGGCCTCATCTTGGGCCTG 289 Ser-227 to ThrTGTTATCTCCTAGGTTGGC T CTGACTGTACCACCATCCACTAC RhabdomyosarcomaAACTACATGTGTAACAGTTCCTGCATGGGCGGCATGATCATGCCGCCCATGCAGGAACTGTTACACATGTAGTTGTAGT 290 GGATGGTGGTACAGTCAG AGCCAACCTAGGAGATAACACAG GCCCAAGATGAGGCCAGTGCGCCTTGGGGAGACCTGTG AGGTTGGC TCTGACTGT 291 ACAGTCAG A GCCAACCT 292 cCAC-AACGCACTGGCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGC 293 His-233 to AsnTCTGACTGTACCACCATC C ACTACAACTACATGTGTAACAGTT GliomaCCTGCATGGGCGGCATGAACCGGAGGCCCATCCTCATGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAGGAACTG 294 TTACACATGTAGTTGTAGT GGATGGTGGTACAGTCAGAGCCA ACCTAGGAGATAACACAGGCCCAAGATGAGGCCAGTGC CCACCATC CACTACAAC 295 GTTGTAGT G GATGGTGG 296 cAAC-GACGCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGAC 297 Asn-235 to AspTGTACCACCATCCACTAC A ACTACATGTGTAACAGTTCCTGCA AdrenocorticalTGGGCGGCATGAACCGGAGGCCCATCCTCACCATCA carcinomaTGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCAG 298 GAACTGTTACACATGTAGT TGTAGTGGATGGTGGTACAGTCA GAGCCAACCTAGGAGATAACACAGGCCCAAGATGAGGC TCCACTAC AACTACATG 299 CATGTAGT T GTAGTGGA 300 AAC-AGCCCTCATCTTGGGCCTGTGTTATCTCCTAGGTTGGCTCTGACT 301 Asn-235 to SerGTACCACCATCCACTACA A CTACATGTGTAACAGTTCCTGCAT RhabdomyosarcomaGGGCGGCATGAACCGGAGGCCCATCCTCACCATCATATGATGGTGAGGATGGGCCTCCGGTTCATGCCGCCCATGCA 302 GGAACTGTTACACATGTAG TTGTAGTGGATGGTGGTACAGTC AGAGCCAACCTAGGAGATAACACAGGCCCAAGATGAGG CCACTACA ACTACATGT 303 ACATGTAG T TGTAGTGG 304 ATCc-ATGCATCCACTACAACTACATGTGTAACAGTTCCTGCATGGGCGG 305 IIe-251 to MetCATGAACCGGAGGCCCAT C CTCACCATCATCACACTGGAAGA GliomaCTCCAGGTCAGGAGCCACTTGCCACCCTGCACACTGGCCAGTGTGCAGGGTGGCAAGTGGCTCCTGACCTGGAGTCTT 306 CCAGTGTGATGATGGTGAG GATGGGCCTCCGGTTCATGCCG CCCATGCAGGAACTGTTACACATGTAGTTGTAGTGGATG AGGCCCAT CCTCACCAT 307 ATGGTGAG G ATGGGCCT 308 ACA-ATAACATGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGG 309 Thr-256 to IleCCCATCCTCACCATCATCA C ACTGGAAGACTCCAGGTCAGGA GlioblastomaGCCACTTGCCACCCTGCACACTGGCCTGCTGTGCCCCATGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGGCTCC 310 TGACCTGGAGTCTTCCAGT GTGATGATGGTGAGGATGGGCCT CCGGTTCATGCCGCCCATGCAGGAACTGTTACACATGT CATCATCA CACTGGAAG 311 CTTCCAGT G TGATGATG 312 CTG-CAGTGTGTAACAGTTCCTGCATGGGCGGCATGAACCGGAGGCCC 313 Leu-257 to GlnATCCTCACCATCATCACAC T GGAAGACTCCAGGTCAGGAGCC Li-Fraumeni syndromeACTTGCCACCCTGCACACTGGCCTGCTGTGCCCCAGCCGGCTGGGGCACAGCAGGCCAGTGTGCAGGGTGGCAAGTGG 314 CTCCTGACCTGGAGTCTTCC AGTGTGATGATGGTGAGGATGG GCCTCCGGTTCATGCCGCCCATGCAGGAACTGTTACACA CATCACAC TGGAAGACT 315 AGTCTTCC A GTGTGATG 316 CTG-CCGGACCTGATTTCCTTACTGCCTCTTGCTTCTCTTTTCCTATCCT 317 Leu-265 to ProGAGTAGTGGTAATCTAC T GGGACGGAACAGCTTTGAGGTGCG Li-Fraumeni syndromeTGTTTGTGCCTGTCCTGGGAGAGACCGGCGCACAGATCTGTGCGCCGGTCTCTCCCAGGACAGGCACAAACACGCAC 318 CTCAAAGCTGTTCCGTCCC AGTAGATTACCACTACTCAGGAT AGGAAAAGAGAAGCAAGAGGCAGTAAGGAAATCAGGTC TAATCTAC TGGGACGGA 319 TCCGTCCC A GTAGATTA 320 gCGT-TGTTGCTTCTCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGAC 321 Arg-273 to CysGGAACAGCTTTGAGGTG C GTGTTTGTGCCTGTCCTGGGAGA Li-Fraumeni syndromeGACCGGCGCACAGAGGAAGAGAATCTCCGCAAGAAAGCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGGTCTCTCC 322 CAGGACAGGCACAAACAC GCACCTCAAAGCTGTTCCGTCCCA GTAGATTACCACTACTCAGGATAGGAAAAGAGAAGCA TTGAGGTG CGTGTTTGT 323 ACAAACAC G CACCTCAA 324 TGT-TATCTTTTCCTATCCTGAGTAGTGGTAATCTACTGGGACGGAACA 325 Cys-275 to TyrGCTTTGAGGTGCGTGTTT G TGCCTGTCCTGGGAGAGACCGG Li-Fraumeni syndromeCGCACAGAGGAAGAGAATCTCCGCAAGAAAGGGGAGCCGGCTCCCCTTTCTTGCGGAGATTCTCTTCCTCTGTGCGCCGG 326 TCTCTCCCAGGACAGGCA CAAACACGCACCTCAAAGCTGTTC CGTCCCAGTAGATTACCACTACTCAGGATAGGAAAAG GCGTGTTT GTGCCTGTC 327 GACAGGCA C AAACACGC 328 CCT-CTTTCCTGAGTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGG 329 Pro-278 to LeuTGCGTGTTTGTGCCTGTC C TGGGAGAGACCGGCGCACAGAG Breast cancerGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGATCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTTCCTCT 330 GTGCGCCGGTCTCTCCCA GGACAGGCACAAACACGCACCTC AAAGCTGTTCCGTCCCAGTAGATTACCACTACTCAGGA TGCCTGTC CTGGGAGAG 331 CTCTCCCA G GACAGGCA 332 AGA-AAAGTAGTGGTAATCTACTGGGACGGAACAGCTTTGAGGTGCGTG 333 Arg-280 to LysTTTGTGCCTGTCCTGGGA G AGACCGGCGCACAGAGGAAGAG GliomaAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTGCCGGCAGCTCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCT 334 TCCTCTGTGCGCCGGTCT CTCCCAGGACAGGCACAAACACG CACCTCAAAGCTGTTCCGTCCCAGTAGATTACCACTAC TCCTGGGA GAGACCGGC 335 GCCGGTCT C TCCCAGGA 336 GAA-GCAGGAACAGCTTTGAGGTGCGTGTTTGTGCCTGTCCTGGGAGA 337 Glu-286 to AlaGACCGGCGCACAGAGGAAG A GAATCTCCGCAAGAAAGGGGA AdrenocorticalGCCTCACCACGAGCTGCCCCCAGGGAGCACTAAGCGAGG carcinomaCCTCGCTTAGTGCTCCCTGGGGGCAGCTCGTGGTGAGGCTC 338 CCCTTTCTTGCGGAGATTC TCTTCCTCTGTGCGCCGGTCTCT CCCAGGACAGGCACAAACACGCACCTCAAAGCTGTTCC AGAGGAAG AGAATCTCC 339 GGAGATTC T CTTCCTCT 340 CGA-CCAAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCTG 341 Arg-306 to ProCCCCCAGGGAGCACTAAGC G AGGTAAGCAAGCAGGACAAGA RhabdomyosarcomaAGCGGTGGAGGAGACCAAGGGTGCAGTTATGCCTCAGATATCTGAGGCATAACTGCACCCTTGGTCTCCTCCACCGCTTCT 342 TGTCCTGCTTGCTTACCT CGCTTAGTGCTCCCTGGGGGCAGC TCGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTT CACTAAGC GAGGTAAGC 343 GCTTACCT C GCTTAGTG 344 gCGA-TGAGAAGAGAATCTCCGCAAGAAAGGGGAGCCTCACCACGAGCT 345 Arg-306 to TermGCCCCCAGGGAGCACTAAG C GAGGTAAGCAAGCAGGACAAG Li-Fraumeni syndromeAAGCGGTGGAGGAGACCAAGGGTGCAGTTATGCCTCAGATCTGAGGCATAACTGCACCCTTGGTCTCCTCCACCGCTTCTT 346 GTCCTGCTTGCTTACCTC GCTTAGTGCTCCCTGGGGGCAGCT CGTGGTGAGGCTCCCCTTTCTTGCGGAGATTCTCTTC GCACTAAG CGAGGTAAG 347 CTTACCTC G CTTAGTGC 348 gCGC-TGCGGTACTGTGAATATACTTACTTCTCCCCCTCCTCTGTTGCTGC 349 Arg-337 to CysAGATCCGTGGGCGTGAG C GCTTCGAGATGTTCCGAGAGCTG OsteosarcomaAATGAGGCCTTGGAACTCAAGGATGCCCAGGCTGGGATCCCAGCCTGGGCATCCTTGAGTTCCAAGGCCTCATTCAGCT 350 CTCGGAACATCTCGAAGC GCTCACGCCCACGGATCTGCAGC AACAGAGGAGGGGGAGAAGTAAGTATATTCACAGTACC GGCGTGAG CGCTTCGAG 351 CTCGAAGC G CTCACGCC 352 CTG-CCGCTCCCCCTCCTCTGTTGCTGCAGATCCGTGGGCGTGAGCGC 353 Leu-344 to ProTTCGAGATGTTCCGAGAGC T GAATGAGGCCTTGGAACTCAAG Li-Fraumeni syndromeGATGCCCAGGCTGGGAAGGAGCCAGGGGGGAGCAGGGCGCCCTGCTCCCCCCTGGCTCCTTCCCAGCCTGGGCATCCTT 354 GAGTTCCAAGGCCTCATTC AGCTCTCGGAACATCTCGAAGCG CTCACGCCCACGGATCTGCAGCAACAGAGGAGGGGGAG CCGAGAGC TGAATGAGG 355 CCTCATTC A GCTCTCGG 356

EXAMPLE 6 Beta Globin

[0114] Hemoglobin, the major protein in the red blood cell, binds oxygenreversibly and is responsible for the cells' capacity to transportoxygen to the tissues. In adults, the major hemoglobin is hemoglobin A,a tetrameric protein consisting of two identical alpha globin chains andtwo beta globin chains. Disorders involving hemoglobin are among themost common genetic disorders worldwide, with approximately 5% of theworld's population being carriers for clinically important hemoglobinmutations. Approximately 300,000 severely affected homozygotes orcompound heterozygotes are born each year.

[0115] Mutation of the glutamic acid at position 7 in beta globin tovaline causes sickle cell anemia, the clinical manifestations of whichare well known. Mutations that cause absence of beta chain causebeta-zero-thalassemia. Reduced amounts of detectable beta globin causesbeta-plus-thalassemia. For clinical purposes, beta-thalassemia isdivided into thalassemia major (transfusion dependent),. thalassemiaintermedia (of intermediate severity), and thalassemia minor(asymptomatic). Patients with thalassemia major present in the firstyear of life with severe anemia; they are unable to maintain ahemoglobin level about 5 gm/dl.

[0116] The beta-thalassemias were among the first human genetic diseasesto be examined by means of recombinant DNA analysis. Baysal et al.,Hemoglobin 19(3-4):213-36 (1995) and others provide a compendium ofmutations that result in beta-thalassemia.

[0117] Hemoglobin disorders were among the first to be considered forgene therapy. Transcriptional silencing of genes transferred intohematopoietic stem cells, however, poses one of the most significantchallenges to its success. If the transferred gene is not completelysilenced, a progressive decline in gene expression is often observed.Position effect variegation (PEV) and silencing mechanisms may act on atransferred globin gene residing in chromatin outside of the normalglobin locus during the important terminal phases of erythroblastdevelopment when globin transcripts normally accumulate rapidly despiteheterochromatization and shutdown of the rest of the genome. Theattached table discloses the correcting oligonucleotide base sequencesfor the beta globin oligonucleotides of the invention. TABLE 12 BetaGlobin Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQID Mutation Correcting Oligos NO: Sickle Cell AnemiaTCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCA 357 GLU-7-VALTGGTGCACCTGACTCCTG A GGAGAAGTCTGCCGTTACTGCC GAG to GTGCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGTGATCACCACCAACTTCATCCACGTTCACCTTGCCCCACAGGGCA 358 GTAACGGCAGACTTCTCC TCAGGAGTCAGGTGCACCATGGT GTCTGTTTGAGGTTGCTAGTGAACACAGTTGTGTCAGA GACTCCTG AGGAGAAGT 359 ACTTCTCC T CAGGAGTC 360 Thalassaemia BetaCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA 361 MET-0-ARGACCTCAAACAGACACCA T GGTGCACCTGACTCCTGAGGAGA ATG to AGGAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC 362 CTCAGGAGTCAGGTGCACC ATGGTGTCTGTTTGAGGTTGCT AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG AGACACCA TGGTGCACC 363 GGTGCACC A TGGTGTCT 364 Thalassaemia BetaTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCAA 365 MET-0-ILECCTCAAACAGACACCAT G GTGCACCTGACTCCTGAGGAGAA ATG to ATAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGCACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCT 366 CCTCAGGAGTCAGGTGCAC CATGGTGTCTGTTTGAGGTTGC TAGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATA GACACCAT GGTGCACCT 367 AGGTGCAC C ATGGTGTC 368 Thalassaemia BetaTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCAA 369 MET-0-ILECCTCAAACAGACACCAT G GTGCACCTGACTCCTGAGGAGAA ATG to ATTGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGCACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCT 370 CCTCAGGAGTCAGGTGCAC CATGGTGTCTGTTTGAGGTTGC TAGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATA GACACCAT GGTGCACCT 371 AGGTGCAC C ATGGTGTC 372 Thalassaemia BetaCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA 373 MET-0-LYSACCTCAAACAGACACCA T GGTGCACCTGACTCCTGAGGAGA ATG to AAGAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC 374 CTCAGGAGTCAGGTGCACC ATGGTGTCTGTTTGAGGTTGCT AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG AGACACCA TGGTGCACC 375 GGTGCACC A TGGTGTCT 376 Thalassaemia BetaCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGCA 377 MET-0-THRACCTCAAACAGACACCA T GGTGCACCTGACTCCTGAGGAGA ATG to ACGAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTACGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTC 378 CTCAGGAGTCAGGTGCACC ATGGTGTCTGTTTGAGGTTGCT AGTGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAG AGACACCA TGGTGCACC 379 GGTGCACC A TGGTGTCT 380 Thalassaemia BetaTCTATTGCTTACATTTGCTTCTGACACAACTGTGTTCACTAGC 381 MET-0-VALAACCTCAAACAGACACC A TGGTGCACCTGACTCCTGAGGAG ATG to GTGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGCGTTCACCTTGCCCCACAGGGCAGTAACGGCAGACTTCTCC 382 TCAGGAGTCAGGTGCACCA TGGTGTCTGTTTGAGGTTGCTAG TGAACACAGTTGTGTCAGAAGCAAATGTAAGCAATAGA CAGACACC ATGGTGCAC 383 GTGCACCA T GGTGTCTG 384 Thalassaemia BetaTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAAGT 385 TRP-16-TermCTGCCGTTACTGCCCTGTG G GGCAAGGTGAACGTGGATGAA TGG to TGAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTATAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTTC 386 ATCCACGTTCACCTTGCC CCACAGGGCAGTAACGGCAGACT TCTCCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGA GCCCTGTG GGGCAAGGT 387 ACCTTGCC C CACAGGGC 388 Thalassaemia BetaCTCAAACAGACACCATGGTGCACCTGACTCCTGAGGAGAAG 389 TRP-16-TermTCTGCCGTTACTGCCCTGT G GGGCAAGGTGAACGTGGATGA TGG to TAGAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAACTTCA 390 TCCACGTTCACCTTGCCC CACAGGGCAGTAACGGCAGACTT CTCCTCAGGAGTCAGGTGCACCATGGTGTCTGTTTGAG TGCCCTGT GGGGCAAGG 391 CCTTGCCC C ACAGGGCA 392 Thalassaemia BetaACAGACACCATGGTGCACCTGACTCCTGAGGAGAAGTCTGC 393 LYS-18-TermCGTTACTGCCCTGTGGGGC A AGGTGAACGTGGATGAAGTTG AAG to TAGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTACAAGCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACCACCAA 394 CTTCATCCACGTTCACCT TGCCCCACAGGGCAGTAACGGCA GACTTCTCCTCAGGAGTCAGGTGCACCATGGTGTCTGT TGTGGGGC AAGGTGAAC 395 GTTCACCT T GCCCCACA 396 Thalassaemia BetaCCATGGTGCACCTGACTCCTGAGGAGAAGTCTGCCGTTACT 397 ASN-20-SERGCCCTGTGGGGCAAGGTGA A CGTGGATGAAGTTGGTGGTGA AAC to AGCGGCCCTGGGCAGGTTGGTATCAAGGTTACAAGACAGGTTAACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCA 398 CCACCAACTTCATCCACG TTCACCTTGCCCCACAGGGCAGTA ACGGCAGACTTCTCCTCAGGAGTCAGGTGCACCATGG CAAGGTGA ACGTGGATG 399 CATCCACG T TCACCTTG 400 Thalassaemia BetaACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGG 401 GLU-23-ALAGGCAAGGTGAACGTGGATG A AGTTGGTGGTGAGGCCCTGG GAA to GCAGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGACGTCTCCTTAAACCTGTCTTGTAACCTTGATACCAACCTGCCC 402 AGGGCCTCACCACCAACT TCATCCACGTTCACCTTGCCCCAC AGGGCAGTAACGGCAGACTTCTCCTCAGGAGTCAGGT CGTGGATG AAGTTGGTG 403 CACCAACT T CATCCACG 404 Thalassaemia BetaCACCTGACTCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTG 405 GLU-23-termGGGCAAGGTGAACGTGGAT G AAGTTGGTGGTGAGGCCCTG GAA to TAAGGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGATCTCCTTAAACCTGTCTTGTAACCTTGATACCAACCTGCCCA 406 GGGCCTCACCACCAACTT CATCCACGTTCACCTTGCCCCACA GGGCAGTAACGGCAGACTTCTCCTCAGGAGTCAGGTG ACGTGGAT GAAGTTGGT 407 ACCAACTT C ATCCACGT 408 Thalassaemia BetaGAGGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAA 409 GLU-27-LYSCGTGGATGCAGTTGGTGGT G AGGCCCTGGGCAGGTTGGTAT GAG to AAGCAAGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACTAGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGATAC 410 CAACCTGCCCAGGGCCT CACCACCAACTGCATCCACGTTCA CTTTGCCCCACAGGGCATTGACAGCAGTCTTCTCCTC TTGGTGGT GAGGCCCTG 411 CAGGGCCT C ACCACCAA 412 Thalassaemia BetaGAGGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAA 413 GLU-27-TermCGTGGATGCAGTTGGTGGT G AGGCCCTGGGCAGGTTGGTAT GAG to TAGCAAGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACTAGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGATAC 414 CAACCTGCCCAGGGCCT CACCACCAACTGCATCCACGTTCA CTTTGCCCCACAGGGCATTGACAGCAGTCTTCTCCTC TTGGTGGT GAGGCCCTG 415 CAGGGCCT C ACCACCAA 416 Thalassaemia BetaGAGAAGACTGCTGTCAATGCCCTGTGGGGCAAAGTGAACGT 417 ALA-28-SERGGATGCAGTTGGTGGTGAG G CCCTGGGCAGGTTGGTATCAA GCC to TCCGGTTATAAGAGAGGCTCAAGGAGGCAAATGGAAACTGGGCCCAGTTTCCATTTGCCTCCTTGAGCCTCTCTTATAACCTTGA 418 TACCAACCTGCCCAGGG CCTCACCACCAACTGCATCCACGT TCACTTTGCCCCACAGGGCATTGACAGCAGTCTTCTC GTGGTGAG GCCCTGGGC 419 GCCCAGGG C CTCACCAC 420 Thalassaemia BetaCTGTCAATGCCCTGTGGGGCAAAGTGAACGTGGATGCAGTT 421 ARG-31-THRGGTGGTGAGGCCCTGGGCA G GTTGGTATCAAGGTTATAAGA AGG to ACGGAGGCTCAAGGAGGCAAATGGAAACTGGGCATGTGTAGATCTACACATGCCCAGTTTCCATTTGCCTCCTTGAGCCTCTCTT 422 ATAACCTTGATACCAAC CTGCCCAGGGCCTCACCACCAACTG CATCCACGTTCACTTTGCCCCACAGGGCATTGACAG CCTGGGCA GGTTGGTAT 423 ATACCAAC C TGCCCAGG 424 Thalassaemia BetaTGGGTTTCTGATAGGCACTGACTCTCTGTCCCTTGGGCTGTT 425 Leu-33-GLNTTCCTACCCTCAGATTAC T GGTGGTCTACCCTTGGACCCAGA CTG to CAGGGTTCTTTGAGTCCTTTGGGGATCTGTCCTCTCCTGATCAGGAGAGGACAGATCCCCAAAGGACTCAAAGAACCTCTG 426 GGTCCAAGGGTAGACCACC AGTAATCTGAGGGTAGGAAAAC AGCCCAAGGGACAGAGAGTCAGTGCCTATCAGAAACCCA CAGATTAC TGGTGGTCT 427 AGACCACC A GTAATCTG 428 Thalassaemia BetaATAGGCACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCT 429 TYR-36-TermCAGATTACTGGTGGTCTA C CCTTGGACCCAGAGGTTCTTTGA TAC to TAAGTCCTTTGGGGATCTGTCCTCTCCTGATGCTGTTATGCATAACAGCATCAGGAGAGGACAGATCCCCAAAGGACTCAAA 430 GAACCTCTGGGTCCAAGG GTAGACCACCAGTAATCTGAGGG TAGGAAAACAGCCCAAGGGACAGAGAGTCAGTGCCTAT GTGGTCTA CCCTTGGAC 431 GTCCAAGG G TAGACCAC 432 Thalassaemia BetaACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGATT 433 TRP-38-TermACTGGTGGTCTACCCTTG G ACCCAGAGGTTCTTTGAGTCCTT TGG to TGATGGGGATCTGTCCTCTCCTGATGCTGTTATGGGCAACGTTGCCCATAACAGCATCAGGAGAGGACAGATCCCCAAAGG 434 ACTCAAAGAACCTCTGGGT CCAAGGGTAGACCACCAGTAATC TGAGGGTAGGAAAACAGCCCAAGGGACAGAGAGTCAGT TACCCTTG GACCCAGAG 435 CTCTGGGT C CAAGGGTA 436 Thalassaemia BetaCACTGACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGAT 437 TRP-38-TermTACTGGTGGTCTACCCTT G GACCCAGAGGTTCTTTGAGTCCT TGG to TAGTTGGGGATCTGTCCTCTCCTGATGCTGTTATGGGCAATTGCCCATAACAGCATCAGGAGAGGACAGATCCCCAAAGGA 438 CTCAAAGAACCTCTGGGTC CAAGGGTAGACCACCAGTAATCT GAGGGTAGGAAAACAGCCCAAGGGACAGAGAGTCAGTG CTACCCTT GGACCCAGA 439 TCTGGGTC C AAGGGTAG 440 Thalassaemia BetaACTCTCTGTCCCTTGGGCTGTTTTCCTACCCTCAGATTACTG 441 GLN-40-TermGTGGTCTACCCTTGGACC C AGAGGTTCTTTGAGTCCTTTGGG CAG-TAGGATCTGTCCTCTCCTGATGCTGTTATGGGCAACCCTATAGGGTTGCCCATAACAGCATCAGGAGAGGACAGATCCCCA 442 AAGGACTCAAAGAACCTCT GGGTCCAAGGGTAGACCACCAG TAATCTGAGGGTAGGAAAACAGCCCAAGGGACAGAGAGT CTTGGACC CAGAGGTTC 443 GAACCTCT G GGTCCAAG 444 Thalassaemia BetaTTGGGCTGTTTTCCTACCCTCAGATTACTGGTGGTCTACCCT 445 GLU-44-TermTGGACCCAGAGGTTCTTT G AGTCCTTTGGGGATCTGTCCTCT GAG to TAGCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCGAGCCTTCACCTTAGGGTTGCCCATAACAGCATCAGGAGAG 446 GACAGATCCCCAAAGGACT CAAAGAACCTCTGGGTCCAAGG GTAGACCACCAGTAATCTGAGGGTAGGAAAACAGCCCAA GGTTCTTT GAGTCCTTT 447 AAAGGACT C AAAGAACC 448 Thalassaemia BetaTTCTTTGAGTCCTTTGGGGATCTGTCCTCTCCTGATGCTGTTA 449 LYS-62-TermTGGGCAACCCTAAGGTG A AGGCTCATGGCAAGAAGGTGCTA AAG to TAGGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCGGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGCACCTAGC 450 ACCTTCTTGCCATGAGCCT TCACCTTAGGGTTGCCCATAACA GCATCAGGAGAGGACAGATCCCCAAAGGACTCAAAGAA CTAAGGTG AAGGCTCAT 451 ATGAGCCT T CACCTTAG 452 Thalassaemia BetaTGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGA 453 SER-73-ARGAGGTGCTAGGTGCCTTTAG T GATGGCCTGGCTCACCTGGAC AGT to AGAAACCTCAAGGGCACTTTTTCTCAGCTGAGTGAGCTGCACGTGCAGCTCACTCAGCTGAGAAAAAGTGCCCTTGAGGTTGTC 454 CAGGTGAGCCAGGCCATC ACTAAAGGCACCTAGCACCTTCT TGCCATGAGCCTTCACCTTAGGGTTGCCCATAACAGCA GCCTTTAG TGATGGCCT 455 AGGCCATC A CTAAAGGC 456 Haemolytic AnaemiaTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAGGTG 457 GLY-75-VALCTAGGTGCCTTTAGTGATG G CCTGGCTCACCTGGACAACCT GGC to GTCCAAGGGCACTTTTTCTCAGCTGAGTGAGCTGCACTGTGATCACAGTGCAGCTCACTCAGCTGAGAAAAAGTGCCCTTGAG 458 GTTGTCCAGGTGAGCCAGG CCATCACTAAAGGCACCTAGCA CCTTCTTGCCATGAGCCTTCACCTTAGGGTTGCCCATAA TAGTGATG GCCTGGCTC 459 GAGCCAGG C CATCACTA 460 Thalassaemia BetaGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGG 461 GLU-91-TermCACCTTTGCCACACTGAGT G AGCTGCACTGTGACAAGCTGC GAG to TAGACGTGGATCCTGAGAACTTCAGGGTGAGTCTATGGGACCGGTCCCATAGACTCACCCTGAAGTTCTCAGGATCCACGTGCA 462 GCTTGTCACAGTGCAGCT CACTCAGTGTGGCAAAGGTGCCC TTGAGGTTGTCCAGGTGAGCCAGGCCATCACTAAAGGC CACTGAGT GAGCTGCAC 463 GTGCAGCT C ACTCAGTG 464 Thalassaemia BetaCTGGACAACCTCAAGGGCACTTTTTCTCAGCTGAGTGAGCTG 465 VAL-99-METCACTGTGACAAGCTGCAC G TGGATCCTGAGAACTTCAGGGT GTG to ATGGAGTCCAGGAGATGCTTCACTTTTCTCTTTTTACTTTCGAAAGTAAAAAGAGAAAAGTGAAGCATCTCCTGGACTCACCC 466 TGAAGTTCTCAGGATCCA CGTGCAGCTTGTCACAGTGCAGCT CACTCAGCTGAGAAAAAGTGCCCTTGAGGTTGTCCAG AGCTGCAC GTGGATCCT 467 AGGATCCA C GTGCAGCT 468 Thalassaemia BetaCCCTTTTGCTAATCATGTTCATACCTCTTATCTTCCTCCCACA 469 LEU-111-PROGCTCCTGGGCAACGTGC T GGTCTGTGTGCTGGCCCATCACT CTG-CCGTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTG 470 ATGGGCCAGCACACAGACC AGCACGTTGCCCAGGAGCTGTG GGAGGAAGATAAGAGGTATGAACATGATTAGCAAAAGGG CAACGTGC TGGTCTGTG 471 CACAGACC A GCACGTTG 472 Thalassaemia BetaGCTAATCATGTTCATACCTCTTATCTTCCTCCCACAGCTCCTG 473 CYS-113-TermGGCAACGTGCTGGTCTG T GTGCTGGCCCATCACTTTGGCAA TGT to TGAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAAATTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCC 474 AAAGTGATGGGCCAGCAC ACAGACCAGCACGTTGCCCAGGA GCTGTGGGAGGAAGATAAGAGGTATGAACATGATTAGC CTGGTCTG TGTGCTGGC 475 GCCAGCAC A CAGACCAG 476 Thalassaemia BetaTCATGTTCATACCTCTTATCTTCCTCCCACAGCTCCTGGGCA 477 LEU-115-PROACGTGCTGGTCTGTGTGC T GGCCCATCACTTTGGCAAAGAAT CTG to CCGTCACCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCT 478 TTGCCAAAGTGATGGGCC AGCACACAGACCAGCACGTTGCC CAGGAGCTGTGGGAGGAAGATAAGAGGTATGAACATGA CTGTGTGC TGGCCCATC 479 GATGGGCC A GCACACAG 480 Thalassaemia BetaTGTTCATACCTCTTATCTTCCTCCCACAGCTCCTGGGCAACG 481 ALA-116-ASPTGCTGGTCTGTGTGCTGG C CCATCACTTTGGCAAAGAATTCA GCC to GACCCCCACCAGTGCAGGCTGCCTATCAGAAAGTGGTGGCGCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAA 482 TTCTTTGCCAAAGTGATGG GCCAGCACACAGACCAGCACGTT GCCCAGGAGCTGTGGGAGGAAGATAAGAGGTATGAACA TGTGCTGG CCCATCACT 483 AGTGATGG G CCAGCACA 484 Thalassaemia BetaTTCCTCCCACAGCTCCTGGGCAACGTGCTGGTCTGTGTGCT 485 GLU-122-TermGGCCCATCACTTTGGCAAA G AATTCACCCCACCAGTGCAGG GAA to TAACTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCGGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCC 486 TGCACTGGTGGGGTGAATT CTTTGCCAAAGTGATGGGCCAG CACACAGACCAGCACGTTGCCCAGGAGCTGTGGGAGGAA TTGGCAAA GAATTCACC 487 GGTGAATT C TTTGCCAA 488 Thalassaemia BetaGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAA 489 GLN-128-PROGAATTCACCCCACCAGTGC A GGCTGCCTATCAGAAAGTGGT CAG to CCGGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTATAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCAC 490 CACTTTCTGATAGGCAGCC TGCACTGGTGGGGTGAATTCTTT GCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGC ACCAGTGC AGGCTGCCT 491 AGGCAGCC T GCACTGGT 492 Thalassaemia BetaGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAA 493 GLN-128-TermAGAATTCACCCCACCAGTG C AGGCTGCCTATCAGAAAGTGGT CAG to TAGGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACC 494 ACTTTCTGATAGGCAGCCT GCACTGGTGGGGTGAATTCTTTG CCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCC CACCAGTG CAGGCTGCC 495 GGCAGCCT G CACTGGTG 496 Thalassaemia BetaGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCA 497 GLN-132-LYSCCAGTGCAGGCTGCCTAT C AGAAAGTGGTGGCTGGTGTGGC CAG to AAGTAATGCCCTGGCCCACAAGTATCACTAAGCTCGCTTTCGAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCC 498 ACACCAGCCACCACTTTCT GATAGGCAGCCTGCACTGGTGG GGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGAC CTGCCTAT CAGAAAGTG 499 CACTTTCT G ATAGGCAG 500

EXAMPLE 7 Retinoblastoma

[0118] Retinoblastoma (RB) is an embryonic neoplasm of retinal origin.It almost always presents in early childhood and is often bilateral. Therisk of osteogenic sarcoma is increased 500-fold in bilateralretinoblastoma patents, the bone malignancy being at sites removed fromthose exposed to radiation treatment of the eye tumor.

[0119] The retinoblastoma susceptibility gene (pRB; pRb) plays a pivotalrole in the regulation of the cell cycle. pRB restrains cell cycleprogression by maintaining a checkpoint in late G₁ that controlscommitment of cells to enter S phase. The critical role that pRB playsin cell cycle regulation explains its status as archetypal tumorsuppressor: loss of pRB function results in an inability to maintaincontrol of the G₁ checkpoint; unchecked progression through the cellcycle is, in turn, a hallmark of neoplasia.

[0120] Blanquet et al., Hum. Molec. Genet 4: 383-388 (1995) performed amutation survey of the RB1 gene in 232 patients with hereditary ornonhereditary retinoblastoma. They systematically explored all 27 exonsand flanking sequences, as well as the promoter. All types of pointmutations were represented and found to be unequally distributed alongthe RB1 gene sequence. In the population studied, exons 3, 8, 18, and 19were preferentially altered. The attached table discloses the correctingoligonucleotide base sequences for the retinoblastoma oligonucleotidesof the invention. TABLE 13 pRB Mutations and Genome-Correcting OligosClinical Phenotype & SEQ ID Mutation Correcting Oligos NO:Retinoblastoma AATATTTGATCTTTATTTTTTGTTCCCAGGGAGGTTATATTCAA 501Trp99Term AAGAAAAAGGAACTGT G GGGAATCTGTATCTTTATTGCAGCA TGG-TAGGTTGACCTAGATGAGATGTCGTTCACTTTTACTGATCAGTAAAAGTGAACGACATCTCATCTAGGTCAACTGCTGCA 502 ATAAAGATACAGATTCCC CACAGTTCCTTTTTCTTTTGAATATA ACCTCCCTGGGAACAAAAAATAAAGATCAAATATT GGAACTGT GGGGAATCT 503 AGATTCCC C ACAGTTCC 504 RetinoblastomaATTTACTTTTTTCTATTCTTTCCTTTGTAGTGTCCATAAATTCTT 505 Glu137AspTAACTTACTAAAAGA A ATTGATACCAGTACCAAAGTTGATAAT GAA-GATGCTATGTCAAGACTGTTGAAGAAGTATGATGTATACATCATACTTCTTCAACAGTCTTGACATAGCATTATCAACTT 506 TGGTACTGGTATCAAT TTCTTTTAGTAAGTTAAAGAATTTATGG ACACTACAAAGGAAAGAATAGAAAAAAGTAAAT CTAAAAGA AATTGATAC 507 GTATCAAT T TCTTTTAG 508 RetinoblastomaTGATTTACTTTTTTCTATTCTTTCCTTTGTAGTGTCCATAAATT 509 Glu137TermCTTTAACTTACTAAAA G AAATTGATACCAGTACCAAAGTTGAT GAA-TAAAATCCTATGTCAAGACTGTTGAAGAAGTATGATGCATCATACTTCTTCAACAGTCTTGACATAGCATTATCAACTTT 510 GGTACTGGTATCAATTT CTTTTAGTAAGTTAAAGAATTTATGG ACACTACAAAGGAAAGAATAGAAAAAGTAAATCA TACTAAAA GAAATTGAT 511 ATCAATTT C TTTTAGTA 512 RetinoblastomaAAAATGTTAAAAAGTCATAATGTTTTTCTTTTCAGGACATGTGA 513 Gln176TermACTTATATATTTGACA C AACCCAGCAGTTCGTAAGTAGTTCAC CAA-TAAAGAATGTTATTTTTCACTTAAAAAAAAAGATTTTAAAATCTTTTTTTTTAAGTGAAAAATAACATTCTGTGAACTACT 514 TACGAACTGCTGGGTT GTGTCAAATATATAAGTTCACATGTCC TGAAAAGAAAAACATTATGACTTTTTAACATTTT ATTTGACA CAACCCAGC 515 GCTGGGTT G TGTCAAAT 516 RetinoblastomaTGATACATTTTTCCTGTTTTTTTTCTGCTTTCTATTTGTTTAATA 517 Ile185ThrGGATATCTACTGAAA T AAATTCTGCATTGGTGCTAAAAGTTTC ATA-ACATTGGATCACATTTTTATTAGCTAAAGGTAAGTTAACTTACCTTTAGCTAATAAAAATGTGATCCAAGAAACTTTTA 518 GCACCAATGCAGAATTT ATTTCAGTAGATATCCTATTAAACAA ATAGAAAGCAGAAAAAAAACAGGAAAAATGTATCA TACTGAAA TAAATTCTG 519 CAGAATTT A TTTCAGTA 520 RetinoblastomaAAAGATCTGAATCTCTAACTTTCTTTAAAAATGTACATTTTTTT 521 Gln207TermTTCAGGGGAAGTATTA C AAATGGAAGATGATCTGGTGATTTC CAA-TAAATTTCAGTTAATGCTATGTGTCCTTGACTATTTTATAAAATAGTCAAGGACACATAGCATTAACTGAAATGAAATCAC 522 CAGATCATCTTCCATTT GTAATACTTCCCCTGAAAAAAAAATG TACATTTTTAAAGAAAGTTAGAGATTCAGATCTTT AAGTATTA CAAATGGAA 523 TTCCATTT G TAATACTT 524 RetinoblastomaGTTCTTATCTAATTTACCACTTTTACAGAAACAGCTGTTATACC 525 Arg251TermCATTAAGGTTCACCT C GAACACCCAGGCGAGGTCAGAACA CGA to TGAGGAGTGCACGGATAGCAAAACAACTAGAAAATGATATATCATTTTCTAGTTGTTTTGCTATCCGTGCACTCCTGTTCTG 526 ACCTCGCCTGGGTGTTC GAGGTGAACCATTAATGGGTATAAC AGCTGTTTCTGTAAAAGTGGTAAATTAGATAAGAAC GTTCACCT CGAACACCC 527 GGGTGTTC G AGGTGAAC 528 RetinoblastomaTTTACCACTTTTACAGAAACAGCTGTTATACCCATTAATGGTT 529 Arg255TermCACCTCGAACACCCAGG C GAGGTCAGAACAGGAGTGCACG CGA to TGAGATAGCAAAACAACTAGAAAATGATACAAGAATTATTGCAATAATTCTTGTATCATTTTCTAGTTGTTTTGCTATCCGTGCA 530 CTCCTGTTCTGACCTC GCCTGGGTGTTCGAGGTGAACCATTA ATGGGTATAACAGCTGTTTCTGTAAAAGTGGTAAA CACCCAGG CGAGGTCAG 531 CTGACCTC G CCTGGGTG 532 RetinoblastomaATTAATGGTTCACCTCGAACACCCAGGCGAGGTCAGAACAG 533 Gln266TermGAGTGCACGGATAGCAAAA C AACTAGAAAATGATACAAGAAT CAA to TAATATTGAAGTTCTCTGTAAAGAACATGAATGTAATATAGCTATATTACATTCATGTTCTTTACAGAGAACTTCAATAATTCTT 534 GTATCATTTTCTAGTT GTTTTGCTATCCGTGCACTCCTGTTCT GACCTCGCCTGGGTGTTCGAGGTGAACCATTAAT TAGCAAAA CAACTAGAA 535 TTCTAGTT G TTTTGCTA 536 RetinoblastomaTGACATGTAAAGGATAATTGTCAGTGACTTTTTTCTTCAAGG 537 Arg320TermTTGAAAATCTTTCTAAA C GATACGAAGAAATTTATCTTAAAAAT CGA to TGAAAAGATCTAGATGCAAGATTATTTTTGGATCATGCATGATCCAAAAATAATCTTGCATCTAGATCTTTATTTTTAAGA 538 TAAATTTCTTCGTATC GTTTAGAAAGATTTTCAACCTTGAAAGA AAAAAGTCACTGACAATTATCCTTTACATGTCA TTTCTAAA CGATACGAA 539 TTCGTATC G TTTAGAAA 540 RetinoblastomaACAAATTGTAAATTTTCAGTATGTGAATGACTTCACTTATTGTT 541 Gln354TermATTTAGTTTTGAAACA C AGAGAACACCACGAAAAAGTAACCTT CAG to TAGGATGAAGAGGTGAATGTAATTCCTCCACACACTCGAGTGTGTGGAGGAATTACATTCACCTCTTCATCAAGGTTAC 542 TTTTTCGTGGTGTTCTCT GTGTTTCAAAACTAAATAACAATAA GTGAAGTCATTCACATACTGAAAATTTACATTTGT TTGAAACA CAGAGAACA 543 TGTTCTCT G TGTTTCAA 544 RetinoblastomaTTTTCAGTATGTGAATGACTTCACTTATTGTTATTTAGTTTTGA 545 Arg358GlyAACACAGAGAACACCA C GAAAAAGTAACCTTGATGAAGAGGT CGA to GGAGAATGTAATTCCTCCACACACTCCAGTTAGGTATGCATACCTAACTGGAGTGTGTGGAGGAATTACATTCACCTCTT 546 CATCAAGGTTACTTTTTC GTGGTGTTCTCTGTGTTTCAAAACT AAATAACAATAAGTGAAGTCATTCACATACTGAAAA GAACACCA CGAAAAAGT 547 ACTTTTTC G TGGTGTTC 548 RetinoblastomaTTTTCAGTATGTGAATGACTTCACTTATTGTTATTTAGTTTTGA 549 Arg358TermAACACAGAGAACACCA C GAAAAAGTAACCTTGATGAAGAGGT CGA to TGAGAATGTAATTCCTCCACACACTCCAGTTAGGTATGCATAGCTAACTGGAGTGTGTGGAGGAATTACATTCACCTCTT 550 CATCAAGGTTACTTTTTC GTGGTGTTCTCTGTGTTTCAAAACT AAATAACAATAAGTGAAGTCATTCACATACTGAAAA GAACACCA CGAAAAAGT 551 ACTTTTTC G TGGTGTTC 552 RetinoblastomaCTGTTATGAACACTATCCAACAATTAATGATGATTTTAAATTCA 553 Ser397TermGCAAGTGATCAACCTT C AGAAAATCTGATTTCCTATTTTAACG TCA to TAATAAGCCATATATGAAACATTATTTATTGTAATATATATTACAATAAATAATGTTTCATATATGGCTTACGTTAAAATA 554 GGAAATCAGATTTTCT GAAGGTTGATCACTTGCTGAATTTAAA ATCATCATTAATTGTTGGATAGTGTTCATAACAG TCAACCTT CAGAAAATC 555 GATTTTCT G AAGGTTGA 556 RetinoblastomaTTTCATAATTGTGATTTTCTAAAATAGCAGGCTCTTATTTTTCT 557 Arg445TermTTTTGTTTGTTTGTAG C GATACAAACTTGGAGTTCGCTTGTAT CGA to TGATACCGAGTAATGGAATCCATGCTTAAATCAGTAATTACTGATTTAAGCATGGATTCCATTACTCGGTAATACAAGCG 558 AACTCCAAGTTTGTATC GCTACAAACAAACAAAAAGAAAAATA AGAGCCTGCTATTTTAGAAAATCACAATTATGAAA GTTTGTAG CGATACAAA 559 TTTGTATC G CTACAAAC 560 RetinoblastomaGCTCTTATTTTTCTTTTTGTTTGTTTGTAGCGATACAAACTTGG 561 Arg455TermAGTTCGCTTGTATTAC C GAGTAATGGAATCCATGCTTAAATCA CGA to TGAGTAAGTTAAAAACAATATAAAAAAATTTCAGCCGCGGCTGAAATTTTTTTATATTGTTTTTAACTTACTGATTTAAGC 562 ATGGATTCCATTACTC GGTAATACAAGCGAACTCCAAGTTTGT ATCGCTACAAACAAACAAAAAGAAAAATAAGAGC TGTATTAC CGAGTAATG 563 CATTACTC G GTAATACA 564 RetinoblastomaATCGAAAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAA 565 Arg552TermATGATAAAACATTTAGAA C GATGTGAACATCGAATCATGGAAT CGA to TGACCCTTGCATGGCTCTCAGTAAGTAGCTAAATAATTGCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGATTCCAT 566 GATTCGATGTTCACATC GTTCTAAATGTTTTATCATTTCTCTTG TCAAGTTGCCTTCTGCTTTGATAAAACTTTCGAT ATTTAGAA CGATGTGAA 567 TTCACATC G TTCTAAAT 568 RetinoblastomaAAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAAATGATA 569 Cys553TermAAACATTTAGAACGATG T GAACATCGAATCATGGAATCCCTTG TGT to TGACATGGCTCTCAGTAAGTAGCTAAATAATTGAAGAATTCTTCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGAT 570 TCCATGATTCGATGTTC ACATCGTTCTAAATGTTTTATCATTTC TCTTGTCAAGTTGCCTTCTGCTTTGATAAAACTT GAACGATG TGAACATCG 571 CGATGTTC A CATCGTTC 572 RetinoblastomaAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGAAATGATAA 573 Glu554TermAACATTTAGAACGATGT G AACATCGAATCATGGAATCCCTTG GAA to TAACATGGCTCTCAGTAAGTAGCTAAATAATTGAAGAAATTTCTTCAATTATTTAGCTACTTACTGAGAGCCATGCAAGGGA 574 TTCCATGATTCGATGTT CACATCGTCTAAATGTTTTATCATTT CTCTTGTCAAGTTGCCTTCTGGTTTGATAAAACT AACGATGT GGAACATCGA 575 TCGATGTT C ACATCGTT 576 RetinoblastomaTACCTGGGAAAATTATGCTTACTAATGTGGTTTTAATTTCATC 577 Ser567LeuATGTTTCATATAGGATT C ACCTTTATTTGATCTTATTAAACAAT TCA to TTACAAAGGACCGAGAAGGACCAACTGATCACCTTGATCAAGGTGATCAGTTGGTCCTTCTCGGTCCTTTGATTGTTTAA 578 TAAGATCAAATAAAGGT GAATCCTATATGAAACATGATGAAAT TAAAACCACATTAGTAAGCATAATTTTCCCAGGTA ATAGGATT CACCTTTAT 579 ATAAAGGT G AATCCTAT 580 RetinoblastomaAATGTGGTTTTAATTTCATCATGTTTCATATAGGATTCACCTTT 581 Gln575TermATTTGATCTTATTAAA C AATCAAAGGACCGAGAAGGACCAACT CAA to TAAGATCACCTTGAATCTGCTTGTCCTCTTAATCTTCGAAGATAAGAGGACAAGCAGATTCAAGGTGATCAGTTGGTC 582 CTTCTCGGTCCTTTGATT GTTTAATAAGATCAAATAAAGGTGA ATCCTATATGAAACATGATGAAATTAAAACCACATT TTATTAAA CAATCAAAG 583 CTTTGATT G TTTAATAA 584 RetinoblastomaATTTCATCATGTTTCATATAGGATTCACCTTTATTTGATCTTAT 585 Arg579TermTAAACAATCAAAGGAC C GAGAAGGACCAACTGATCACCTTGA CGA to TGAATCTGCTTGTCCTCTTAATCTTCCTCTCCAGAATATATTCTGGAGAGGAAGATTAAGAGGACAAGCAGATTCAAGGT 586 GATCAGTTGGTCCTTCTC GGTCCTTTGATTGTTTAATAAGATC AAATAAAGGTGAATCCTATATGAAACATGATGAAAT CAAAGGAC CGAGAAGGA 587 TCCTTCTC G GTCCTTTG 588 RetinoblastomaTCATCATGTTTCATATAGGATTCACCTTTATTTGATCTTATTAA 589 Glu580TermACAATCAAAGGACCGA G AAGGACCAACTGATCACCTTGAATC GAA to TAATGCTTGTCCTCTTAATCTTCCTCTCCAGAATAATCGATTATTCTGGAGAGGAAGATTAAGAGGACAAGCAGATTCAA 590 GGTGATCAGTTGGTCCTT CTCGGTCCTTTGATTGTTTAATAAG ATCAAATAAAGGTGAATCCTATATGAAACATGATGA AGGACCGA GAAGGACCA 591 TGGTCCTT C TCGGTCCT 592 RetinoblastomaAGAAAAAAGGTTCAACTACGCGTGTAAATTCTACTGCAAATG 593 Ser634TermCAGAGACACAAGCAACCT C AGCCTTCCAGACCCAGAAGCCA TCA to TGATTGAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGGCCTTTTTTATAAAACAGTGAAAGAGAGGTAGATTTCAATGGCT 594 TCTGGGTCTGGAAGGCT GAGGTTGCTTGTGTCTCTGCATTTG CAGTAGAATTTACACGCGTAGTTGAACCTTTTTTCT AGCAACCT CAGCCTTCC 595 GGAAGGCT G AGGTTGCT 596 RetinoblastomaAAAAAAGGTTCAACTACGCGTGTAAATTCTACTGCAAATGCA 597 Ala635ProGAGACACAAGCAACCTCA G CCTTCCAGACCCAGAAGCCATT GCC to CCCGAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGGTTAACCTTTTTTATAAAACAGTGAAAGAGAGGTAGATTTCAATGG 598 CTTCTGGGTCTGGAAGG CTGAGGTTGCTTGTGTCTCTGCATT TGCAGTAGAATTTACACGCGTAGTTGAACCTTTTTT CAACCTCA GCCTTCCAG 599 CTGGAAGG C TGAGGTTG 600 RetinoblastomaACTACGCGTGTAAATTCTACTGCAAATGCAGAGACACAAGCA 601 Gln639TermACCTCAGCCTTCCAGACC C AGAAGCCATTGAAATCTACCTCT CAG to TAGCTTTCACTGTTTTATAAAAAAGGTTAGTAGATGATTATAATCATCTACTAACCTTTTTTATAAAACAGTGAAAGAGAGGT 602 AGATTTCAATGGCTTCT GGGTCTGGAAGGCTGAGGTTGCTTG TGTCTCTGCATTTGCAGTAGAATTTACACGCGTAGT TCCAGACC CAGAAGCCA 603 TGGCTTCT G GGTCTGGA 604 RetinoblastomaTTGTAATTCAAAATGAACAGTAAAAATGACTAATTTTTCTTATT 605 Leu657ProCCCACAGTGTATCGGC T AGCCTATCTCCGGCTAAATACACTT CTA to CCATGTGAACGCCTTCTGTCTGAGCACCCAGAATTAGATCTAATTCTGGGTGCTCAGACAGAAGGCGTTCACAAAGTGTA 606 TTTAGCCGGAGATAGGCT AGCCGATACACTGTGGGAATAAG AAAAATTAGTCATTTTTACTGTTCATTTTGAATTACAA GTATCGGC TAGCCTATC 607 GATAGGCT A GCCGATAC 608 RetinoblastomaAATGAACAGTAAAAATGACTAATTTTTCTTATTCCCACAGTGTA 609 Arg661TrpTCGGCTAGCCTATCTC C GGCTAAATACACTTTGTGAACGCCT CGG to TGGTCTGTCTGAGCACCCAGAATTAGAACATATCATCTAGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGGCGTT 610 CACAAAGTGTATTTAGCC GGAGATAGGCTAGCCGATACACTG TGGGAATAAGAAAAATTAGTCATTTTTACTGTTCATT CCTATCTC CGGCTAAAT 611 ATTTAGCC G GAGATAGG 612 RetinoblastomaAACAGTAAAAATGACTAATTTTTCTTATTCCCACAGTGTATCG 613 Leu662ProGCTAGCCTATCTCCGGC T AAATACACTTTGTGAACGCCTTCT CTA to CCAGTCTGAGCACCCAGAATTAGAACATATCATCTGGACGTCCAGATGATATGTTCTAATTCTGGGTGCTCAGACAGAAGG 614 CGTTCACAAAGTGTATTT AGCCGGAGATAGGCTAGCCGATAC ACTGTGGGAATAAGAAAAATTAGTCATTTTTACTGTT TCTCCGGC TAAATACAC 615 GTGTATTT A GCCGGAGA 616 RetinoblastomaTATCGGCTAGCCTATCTCCGGCTAAATACACTTTGTGAACGC 617 Glu675TermCTTCTGTGTGAGCACCCA G AATTAGAACATATCATCTGGACC GAA to TAACTTTTCCAGCACACCCTGCAGAATGAGTATGAACTCATGAGTTCATACTCATTCTGCAGGGTGTGCTGGAAAAGGGTCC 618 AGATGATATGTTCTAATT CTGGGTGCTCAGACAGAAGGCGTT CACAAAGTGTATTTAGCCGGAGATAGGCTAGCCGATA AGCACCCA GAATTAGAA 619 TTCTAATT C TGGGTGCT 620 RetinoblastomaTTTGTGAACGCCTTCTGTCTGAGCACCCAGAATTAGAACATA 621 Gln685ProTCATCTGGACCCTTTTCC A GCACACCCTGCAGAATGAGTATG GAG to CCGAACTCATGAGAGACAGGCATTTGGACCAAGTAAGAAATTTCTTACTTGGTCCAAATGCCTGTCTCTCATGAGTTCATACT 622 CATTCTGCAGGGTGTG CTGGAAAAGGGTCCAGATGATATGTT CTAATTCTGGGTGCTCAGACAGAAGGCGTTCACAAA CCTTTTCCA GCACACCC 623 GGGTGTGC T GGAAAAGG 624 RetinoblastomaAAAACCATGTAATAAAATTCTGACTACTTTTACATCAATTTATT 625 Cys706TyrTACTAGATTATGATGT G TTCCATGTATGGCATATGCAAAGTGA TGT to TATAGAATATAGACCTTAAATTCAAAATCATTGTAACGTTACAATGATTTTGAATTTAAGGTCTATATTCTTCACTTTGCA 626 TATGCCATACATGGAA CACATCATAATCTAGTAAATAAATTGA TGTAAAAGTAGTCAGAATTTTATTACATGGTTTT TATGATGT GTTCCATGT 627 ACATGGAA C ACATCATA 628 RetinoblastomaTTCTGACTACTTTTACATCAATTTATTTACTAGATTATGATGTG 629 Cys712ArgTTCCATGTATGGCATA T GCAAAGTGAAGAATATAGACCTTAAA TGC to CGCTTCAAAATCATTGTAACAGCATACAAGGATCTTCGAAGATCCTTGTATGCTGTTACAATGATTTTGAATTTAAGGTC 630 TATATTCTTCACTTTGC ATATGCCATACATGGAACACATCATA ATCTAGTAAATAAATTGATGTAAAAGTAGTCAGAA ATGGCATA TGCPAAGTG 631 CACTTTGC A TATGCCAT 632 RetinoblastomaGTATGGCATATGCAAAGTGAAGAATATAGACCTTAAATTCAAA 633 Tyr728TermATCATTGTAACAGCATA C AAGGATCTTCCTCATGCTGTTCAG TAC to TAAGAGGTAGGTAATTTTCCATAGTAAGTTTTTTTGATATATCAAAAAAACTTACTATGGAAAATTACCTACCTCCTGAACA 634 GCATGAGGAAGATCCTT GTATGCTGTTACAATGATTTTGAATT TAAGGTCTATATTCTTCACTTTGCATATGCCATAC ACAGCATA CAAGGATCT 635 AGATCCTT G TATGCTGT 636 RetinoblastomaTTTTTTTTTTTTTTTACTGTTCTTCCTCAGACATTCAAACGTGT 637 Glu748TermTTTGATCAAAGAAGAG G AGTATGATTCTATTATAGTATTCTATA GAG to TAGACTCGGTCTTCATGCAGAGACTGAAAACAAATATATTTGTTTTCAGTCTCTGCATGAAGACCGAGTTATAGAATAC 638 TATAATAGAATCATACT CCTCTTCTTTGATCAAAACACGTTTGA ATGTCTGAGGAAGAACAGTAAAAAAAAAAAAAAA AAGAAGAG GAGTATGAT 639 ATCATACT C CTCTTCTT 640 RetinoblastomaGTTTTGATCAAAGAAGAGGAGTATGATTCTATTATAGTATTCT 641 Gln762TermATAACTCGGTCTTCATG C AGAGACTGAAAACAAATATTTTGCA GAG to TAGGTATGCTTCCACCAGGGTAGGTCAAAAGTATCCTTAAGGATACTTTTGACCTACCCTGGTGGAAGCATACTGCAAAA 642 TATTTGTTTTCAGTCTCT GCATGAAGACCGAGTTATAGAATAC TATAATAGAATCATACTCCTCTTCTTTGATCAAAAC TCTTCATG CAGAGACTG 643 CAGTCTCT G CATGAAGA 644 RetinoblastomaTAATCTACTTTTTTGTTTTTGCTCTAGCCCCCTACCTTGTCAC 645 Arg787TermCAATACCTCACATTCCT C GAAGCCCTTACAAGTTTCCTAGTTC CGA-TGAACCCTTACGGATTCCTGGAGGGAACATCTATATTTAAATATAGATGTTCCCTCCAGGAATCCGTAAGGGTGAACTAG 646 GAAACTTGTAAGGGCTTC GAGGAATGTGAGGTATTGGTGACA AGGTAGGGGGCTAGAGCAAAAACAAAAAAGTAGATTA ACATTCCT CGAAGCCCT 647 AGGGCTTC G AGGAATGT 648 RetinoblastomaCCTTACGGATTCCTGGAGGGAACATCTATATTTCACCCCTGA 649 Ser816TermAGAGTCCATATAAAATTT C AGAAGGTCTGCCAACACCAACAA TCA to TGAAAATGACTCCAAGATCAAGGTGTGTGTTTTCTCTTTATAAAGAGAAAACACACACCTTGATCTTGGAGTCATTTTTGTTG 650 GTGTTGGCAGACCTTCT GAAATTTTATATGGACTCTTCAGGG GTGAAATATAGATGTTCCCTCCAGGAATCCGTAAGG TAAAATTT CAGAAGGTC 651 GACCTTCT G AAATTTTA 652

EXAMPLE 8 BRCA1 and BRCA2

[0121] Breast cancer is the second major cause of cancer death inAmerican women, with an estimated 44,190 lives lost (290 men and 43,900women) in the US in 1997. While ovarian cancer accounts for fewer deathsthan breast cancer, it still represents 4% of all female cancers. In1994, two breast cancer susceptibility genes were identified: BRCA1 onchromosome 17 and BRCA2 on chromosome 13. When a woman carries amutation in either BRCA1 or BRCA2, she is at increased risk of beingdiagnosed with breast or ovarian cancer at some point in her life.

[0122] Ford et al, Am. J. Hum. Genet. 62: 676-689 (1998) assessed thecontribution of BRCA1 and BRCA2 to inherited breast cancer by linkageand mutation analysis in 237 families, each with at least 4 cases ofbreast cancer. Families were included without regard to the occurrenceof ovarian or other cancers. Overall, disease was linked to BRCA1 in anestimated 52% of families, to BRCA2 in 32% of families, and to neithergene in 16%, suggesting other predisposition genes. The majority (81%)of the breast-ovarian cancer families were due to BRCA1, with mostothers (14%) due to BRCA2. Conversely, the majority (76%) of familieswith both male and female breast cancer were due to BRCA2. The largestproportion (67%) of families due to other genes were families with 4 or5 cases of female breast cancer only.

[0123] More than 75% of the reported mutations in the BRCA1 gene resultin truncated proteins. Couch et al., Hum. Mutat. 8: 8-18,1996. (1996)reported a total of 254 BRCA1 mutations, 132 (52% of which were unique.A total of 221 (87%) of all mutations or 107 (81%) of the uniquemutations are small deletions, insertions, nonsense point mutations,splice variants, and regulatory mutations that result in truncation orabsence of the BRCA1 protein. A total of 11 disease-associated missensemutations (5 unique) and 21 variants (19 unique) as yet unclassified asmissense mutations or polymorphisms had been detected. Thirty-fiveindependent benign polymorphisms had been described. The most commonmutations were 185delAG and 5382insC, which accounted for 30 (11.7%) and26 (10.1%), respectively, of all the mutations.

[0124] Most BRCA2 mutations are predicted to result in a truncatedprotein product. The smallest known cancer-associated deletion removesfrom the C terminus only 224 of the 3,418 residues constituting BRCA2,suggesting that these terminal amino acids are critical for BRCA2function. Studies (Spain et al., Proc. Natl. Acad. Sci. 96:13920-13925(1999)) suggest that such truncations eliminate or interfere with 2nuclear localization signals that reside within the final 156 residuesof BRCA2, suggesting that the vast majority of BRCA2 mutants arenonfunctional because they are not translocated into the nucleus.

[0125] The attached table discloses the correcting oligonucleotide basesequences for the BRACA1 and BRACA2 oligonucleotides of the invention.TABLE 14 BRCA1 Mutations and Genome-Correcting Oligos Clinical Phenotype& SEQ ID Mutation Correcting Oligos NO: Breast CancerCTGCGCTCAGGAGGCCTTCACCCTCTGCTCTGGGTAAAGTT 653 Met-1-IleCATTGGAACAGAAAGAAAT G GATTTATCTGCTCTTCGCGTTG ATG to ATTAAGAAGTACAAAATGTCATTAATGCTATGCAGAAAATCGATTTTCTGCATAGCATTAATGACATTTTGTACTTCTTCAACG 654 CGAAGAGCAGATAAATC CATTTCTTTCTGTTCCAATGAACTTT ACCCAGAGCAGAGGGTGAAGGCCTCCTGAGCGCAG AAAGAAAT GGATTTATC 655 GATAAATC C ATTTCTTT 656 Breast CancerCTGGGTAAAGTTCATTGGAACAGAAAGAAATGGATTTATCTG 657 Val-11-AlaCTCTTCGCGTTGAAGAAG T ACAAAATGTCATTAATGCTATGCA GTA to GCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATATCAACTCCAGACAGATGGGACACTCTAAGATTTTCTGCATA 658 GCATTAATGACATTTTGT ACTTCTTCAACGCGAAGAGCAGATA AATCCATTTCTTTCTGTTCCAATGAACTTTACCCAG TGAAGAAG TACAAAATG 659 CATTTTGT A CTTCTTCA 660 Breast CancerATGGATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCA 661 Ile-21-ValTTAATGCTATGCAGAAA A TCTTAGAGTGTCCCATCTGTCTGG ATC to GTCAGTTGATCAAGGAACCTGTCTCCACAAAGTGTGACCGGTCACACTTTGTGGAGACAGGTTCCTTGATCAACTCCAGAC 662 AGATGGGACACTCTAAGA TTTTCTGCATAGCATTAATGACATT TTGTACTTCTTCAACGCGAAGAGCAGATAAATCCAT TGCAGAAA ATCTTAGAG 663 CTCTAAGA T TTTCTGCA 664 Breast CancerATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAA 665 Leu-22-SerTGCTATGCAGAAAATCT T AGAGTGTCCCATCTGTCTGGAGTT TTA to TCAGATCAAGGAACCTGTCTCCACAAAGTGTGACCACATATGTGGTCACACTTTGTGGAGACAGGTTCCTTGATCAACTCC 666 AGACAGATGGGACACTCT AAGATTTTCTGCATAGCATTAATG ACATTTTGTACTTCTTCAACGCGAAGAGCAGATAAAT GAAAATCT TAGAGTGTC 667 GACACTCT A AGATTTTC 668 Breast CancerAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGG 669 Cys-39-TyrAACCTGTCTCCACAAAGT G TGACCACATATTTTGCAAATTTTG TGT to TATCATGCTGAAACTTCTCAACCAGAAGAAAGGGCCTTCGAAGGCCCTTTCTTCTGGTTGAGAAGTTTCAGCATGCAAAAT 670 TTGCAAAATATGTGGTCA CACTTTGTGGAGACAGGTTCCTTG ATCAACTCCAGACAGATGGGACACTCTAAGATTTTCT CACAAAGT GTGACCACA 671 TGTGGTCA C ACTTTGTG 672 Breast CancerCACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAACCAGA 673 Cys-61-GlyAGAAAGGGCCTTCACAG T GTCCTTTATGTAAGAATGATATAAC TGT to GGTCAAAAGGAGCCTACAAGAAAGTACGAGATTTAGTCGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTTGGTTATATC 674 ATTCTTACATAAAGGAC ACTGTGAAGGCCCTTTCTTCTGGTT GAGAAGTTTCAGCATGCAAAATTTGCAAAATATGTG CTTCACAG TGTCCTTTA 675 TAAAGGAC A CTGTGAAG 676 Breast CancerTTTGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGG 677 Leu-63-StopGCCTTCACAGTGTCCTTT A TGTAAGAATGATATAACCAAAAGG TTA to TAAAGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTTGG 678 TTATATCATTCTTACAT AAAGGACACTGTGAAGGCCCTTTCTT CTGGTTGAGAAGTTTCAGCATGCAAAATTTGCAAA GTGTCCTT TATGTAAGA 679 TCTTACAT A AAGGACAC 680 Breast CancerTGCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGGG 681 Cys-64-ArgCCTTCACAGTGTCCTTTA T GTAAGAATGATATAACCAAAAGGA TGT to CGTGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTG Breast CancerCAACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTTT 682 Cys-64-GlyGGTTATATCATTCTTAC A TAAAGGACACTGTGAAGGCCCTTTC TGT to GGTTTCTGGTTGAGAAGTTTCAGCATGCAAAATTTGCA GTCCTTTA T GTAAGAAT 683 ATTCTTAC ATAAAGGAC 684 Breast Cancer GCAAATTTTGCATGCTGAAACTTCTCAACCAGAAGAAAGGGC685 Cys-64-Tyr CTTCACAGTGTCCTTTAT G TAAGAATGATATAACCAAAAGGAG TGT to TATCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGATCAACAAGTTGACTAAATCTCGTACTTTCTTGTAGGCTCCTTT 686 TGGTTATATCATTCTTA CATAAAGGACACTGTGAAGGCCCTTT CTTCTGGTTGAGAAGTTTCAGCATGCAAAATTTGC TCCTTTAT GTAAGAATG 687 CATTCTTA C ATAAAGGA 688 Breast CancerCAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGAT 689 Gln-74-StopATAACCAAAAGGAGCCTA C AAGAAAGTACGAGATTTAGTCAA CAA to TAACTTGTTGAAGAGCTATTGAAAATCATTTGTGCTTTTCGAAAAGCACAAATGATTTTCAATAGCTCTTCAACAAGTTGACT 690 AAATCTCGTACTTTCTT GTAGGCTCCTTTTGGTTATATCATTCT TACATAAAGGACACTGTGAAGGCCCTTTCTTCTG GGAGCCTA CAAGAAAGT 691 ACTTTCTT G TAGGCTCC 692 Breast CancerAGCTATTGAAAATCATTTGTGCTTTTCAGCTTGACACAGGTTT 693 Tyr-105-CysGGAGTATGCAAACAGCT A TAATTTTGCAAAAAAGGAAAATAAC TAT to TGTTCTCCTGAACATCTAAAAGATGAAGTTTCTATCATATGATAGAAACTTCATCTTTTAGATGTTCAGGAGAGTTATTTT 694 CCTTTTTTGCAAAATTA TAGCTGTTTGCATACTCCAAACCTGT GTCAAGCTGAAAAGCACAAATGATTTTCAATAGCT AAACAGCT ATAATTTTG 695 CAAAATTA T AGCTGTTT 696 Breast CancerCTACAGAGTGAACCCGAAAATCCTTCCTTGCAGGAAACCAGT 697 Asn-158-TyrCTCAGTGTCCAACTCTCT A ACCTTGGAACTGTGAGAACTCTG AAC to TACAGGACAAAGCAGCGGATACAACCTCAAAAGACGTCTGCAGACGTCTTTTGAGGTTGTATCCGCTGCTTTGTCCTCAGAG 698 TTCTCACAGTTCCAAGGT TAGAGAGTTGGACACTGAGACTGG TTTCCTGCAAGGAAGGATTTTCGGGTTCACTCTGTAG AACTCTCT AACCTTGGA 699 TCCAAGGT T AGAGAGTT 700 Breast CancerGAAACCAGTCTCAGTGTCCAACTCTCTAACCTTGGAACTGTG 701 Gln-169-StopAGAACTCTGAGGACAAAG C AGCGGATACAACCTCAAAAGAC CAG to TAGGTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAGCTTCAGAAGAATCAGATCCCAATTCAATGTAGACAGACGTCTT 702 TTGAGGTTGTATCCGCT GCTTTGTCCTCAGAGTTCTCACAGT TCCAAGGTTAGAGAGTTGGACACTGAGACTGGTTTC GGACAAAG CAGCGGATA 703 TATCCGCT G CTTTGTCC 704 Breast CancerCTCCCAGCACAGAAAAAAAGGTAGATCTGAATGCTGATCCCC 705 Trp-353-StopTGTGTGAGAGAAAAGAAT G GAATAAGCAGAAACTGCCATGCT TGG to TAGCAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGATATCCAAGGAACATCTTCAGTATCTCTAGGATTCTCTGAGCAT 706 GGCAGTTTCTGCTTATTC CATTCTTTTCTCTCACACAGGGGAT CAGCATTCAGATCTACCTTTTTTTCTGTGCTGGGAG AAAAGAAT GGAATAAGC 707 GCTTATTC C ATTCTTTT 708 Breast CancerATGCTCAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGAT 709 Ile-379-MetAACACTAAATAGCAGCAT T CAGAAAGTTAATGAGTGGTTTTCC ATT to ATGAGAAGTGATGAACTGTTAGGTTCTGATGACTCACATATGTGAGTCATCAGAACCTAACAGTTCATCACTTCTGGAAAAC 710 CACTCATTAACTTTCTG AATGCTGCTATTTAGTGTTATCCAAG GAACATCTTCAGTATCTCTAGGATTCTCTGAGCAT AGCAGCAT TCAGAAAGT 711 ACTTTCTG A ATGCTGCT 712 Breast CancerGGGAGTCTGAATCAAATGCCAAAGTAGCTGATGTATTGGACG 713 Glu-421-GlyTTCTAAATGAGGTAGATG A ATATTCTGGTTCTTCAGAGAAAAT GAA to GGAAGACTTACTGGCCAGTGATCCTCATGAGGCTTTAATATTAAAGCCTCATGAGGATCACTGGCCAGTAAGTCTATTTTCT 714 CTGAAGAACCAGAATAT TCATCTACCTCATTTAGAACGTCCAA TACATCAGCTACTTTGGCATTTGATTCAGACTCCC GGTAGATG AATATTCTG 715 CAGAATAT T CATCTACC 716 Breast CancerATATGTAAAAGTGAAAGAGTTCACTCCAAATCAGTAGAGAGTA 717 Phe-461-LeuATATTGAAGACAAAATA T TTGGGAAAACCTATCGGAAGAAGG TTT to CTTCAAGCCTCCCCAACTTAAGCCATGTAACTGAAAATCGATTTTCAGTTACATGGCTTAAGTTGGGGAGGCTTGCCTTCT 718 TCCGATAGGTTTTCCCAA ATATTTTGTCTTCAATATTACTCTCT ACTGATTGGAGTGAACTCTTTCACTTTTACATAT ACAAAATA TTTGGGAAA 719 TTTCCCAA A TATTTTGT 720 Breast CancerGAAAGAGTTCACTCCAAATCAGTAGAGAGTAATATTGAAGAC 721 Tyr-465-LeuAAAATATTTGGGAAAACC T ATCGGAAGAAGGCAAGCCTCCCC TAT to GATAACTTAAGCCATGTAACTGAAAATCTAATTATAGGAGCTCCTATAATTAGATTTTCAGTTACATGGCTTAAGTTGGGGAG 722 GCTTGCCTTCTTCCGAT AGGTTTTCCCAAATATTTTGTCTTCA ATATTACTCTCTACTGATTTGGAGTGAACTCTTTC GGAAAACC TATCGGAAG 723 CTTCCGAT A GGTTTTCC 724 Breast CancerACCTATCGGAAGAAGGCAAGCCTCCCCAACTTAAGCCATGTA 725 Gly-484-StopACTGAAAATCTAATTATA G GAGCATTTGTTACTGAGCCACAGA GGA to TGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGCGCTTTAATTTATTTGTGAGGGGACGCTCTTGTATTATCTGTGG 726 CTCAGTAACAAATGCTC CTATAATTAGATTTTCAGTTACATGG CTTAAGTTGGGGAGGCTTGCCTTCTTCCGATAGGT TAATTATA GGAGCATTT 727 AAATGCTC C TATAATTA 728 Breast CancerTTACTGAGCCACAGATAATACAAGAGCGTCCCCTCACAAATA 729 Arg-507-IleAATTAAAGCGTAAAAGGA G ACCTACATCAGGCCTTCATCCTG AGA to ATAAGGATTTTATCAAGAAAGCAGATTGGCAGTTCAAAATTTTGAACTGCCAAATCTGCTTTCTTGATAAAATCCTCAGGAT 730 GAAGGCCTGATGTAGGT CTCCTTTTACGCTTTAATTTATTTGT GAGGGGACGCTCTTGTATTATCTGTGGCTCAGTAA TAAAAGGA GACCTACAT 731 ATGTAGGT C TCCTTTTA 732 Breast CancerCACAGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGC 733 Ser-510-StopGTAAAAGGAGACCTACAT C AGGCCTTCATCCTGAGGATTTTA TCA to TGATCAAGAAAGCAGATTTGGCAGTTCAAAAGACTCCTGATCAGGAGTCTTTTGAACTGCCAAATCTGCTTTCTTGATAAAAT 734 CCTCAGGATGAAGGCCT GATGTAGGTCTCCTTTTACGCTTTA ATTTATTTGTGAGGGGACGCTCTTGTATTATCTGTG ACCTACAT CAGGCCTTC 735 GAAGGCCT G ATGTAGGT 736 Breast CancerAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAG 737 Gln-526-StopAAAGCAGATTTGGCAGTT C AAAAGACTCCTGAAATGATAAATC CAA to TAAAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGATCACTTGACCATTCTGCTCCGTTTGGTTAGTTCCCTGATTTAT 738 CATTTCAGGAGTCTTTT GAACTGCCAAATCTGCTTTCTTGATA AAATCCTCAGGATGAAGGCCTGATGTAGGTCTCCT TGGCAGTT CAAAAGACT 739 AGTCTTTT G AACTGCCA 740 Breast CancerAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAG 741 Gln-541-StopAAAGCAGATTTGGCAGTT C AAAAGACTCCTGAAATGATAAATC CAG to TAGAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGATCACTTGACCATTCTGCTCCGTTTGGTTAGTTCCCTGATTTAT 742 CATTTCAGGAGTCTTTT GAACTGCCAAATCTGCTTTCTTGATA AAATCCTCAGGATGAAGGCCTGATGTAGGTCTCCT AAACGGAG CAGAATGGT 743 ACCATTCT G CTCCGTTT 744 Breast CancerTAAATCAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGA 745 Gly-552-ValTGAATATTACTAATAGTG G TCATGAGAATAAAACAAAAGGTGA GGT to GTTTTCTATTCAGAATGAGAAAAATCCTAACCCAATAGATCTATTGGGTTAGGATTTTTCTCATTCTGAATAGAATCACCTTT 746 TGTTTTATTCTCATGA CCACTATTAGTAATATTCATCACTTGAC CATTCTGCTCCGTTTGGTTAGTTCCCTGATTTA TAATAGTG GTCATGAGA 747 TCTCATGA C CACTATTA 748 Breast CancerGGTCAAGTGATGAATATTACTAATAGTGGTCATGAGAATAAAA 749 Gln-563-StopCAAAAGGTGATTCTATT C AGAATGAGAAAAATCCTAACCCAAT CAG to TAGAGAATCACTCGAAAAAGAATCTGCTTTCAAAACGATCGTTTTGAAAGCAGATTCTTTTTCGAGTGATTCTATTGGGTT 750 AGGATTTTTCTCATTCT GAATAGAATCACCTTTTGTTTTATTCT CATGACCACTATTAGTAATATTCATCACTTGACC ATTCTATT CAGAATGAG 751 CTCATTCT G AATAGAAT 752 Ovarian CancerATAAGCAGCAGTATAAGCAATATGGAACTCGAATTAAATATCC 753 Lys-607-StopACAATTCAAAAGCACCT A AAAAGAATAGGCTGAGGAGGAAGT AAA to TAACTTCTACCAGGCATATTCATGCGCTTGAACTAGTAGCTACTAGTTCAAGCGCATGAATATGCCTGGTAGAAGACTTCC 754 TCCTCAGCCTATTCTTTT TAGGTGCTTTTGAATTGTGGATATT TAATTCGAGTTCCATATTGCTTATACTGCTGCTTAT AAGCACCT AAAAAGAAT 755 ATTCTTTT T AGGTGCTT 756 Breast CancerATATTCATGCGCTTGAACTAGTAGTCAGTAGAAATCTAAGCCC 757 Leu-639-StopACCTAATTGTACTGAAT T GCAAATTGATAGTTGTTCTAGCAGT TTG to TAGGAAGAGATAAAGAAAAAAAAGTACAACCAAATGCCGGCATTTGGTTGTACTTTTTTTTCTTTATCTCTTCACTGCTAGA 758 ACAACTATCAATTTGC AAHCAGTACAATTAGGTGGGCTTAGA TTTCTACTGACTACTAGTTCAAGCGCATGAATAT TACTGAAT TGCAAATTG 759 CAATTTGC A ATTCAGTA 760 Breast CancerGAACCTGCAACTGGAGCCAAGAAGAGTAACAAGCCAAATGAA 761 Asp-693-AsnCAGACAAGTAAAAGACAT G ACAGCGATACTTTCCCAGAGCTG GAC to AACAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGTTAACACTTAGTAAAAGAACCAGGTGCATTTGTTAACTTCAGCTC 762 TGGGAAAGTATCGCTGT CATGTCTTTTACTTGTCTGTTCATTT GGCTTGTTACTCTTCTTGGCTCCAGTTGCAGGTTC AAAGACAT GACAGCGAT 763 ATCGCTGT C ATGTCTTT 764 Ovarian CancerCTGAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGTTCAA 765 Glu-720-StopATACCAGTGAACTTAAA G AATTTGTCAATCCTAGCCTTCCAAG GAA to TAAAGAAGAAAAAGAAGAGAAACTAGAAACAGTTAAAGCTTTAACTGTTTCTAGTTTCTCTTCTTTTTCTTCTCTTGGAAGG 766 CTAGGATTGACAAATT CTTTAAGTTCACTGGTATTTGAACACT TAGTAAAAGAACCAGGTGCATTTGTTAACTTCAG AACTTAAA GAATTTGTC 767 GACAAATT C TTTAAGTT 768 Breast CancerCTAGAAACAGTTAAAGTGTCTAATAATGCTGAAGACCCCAAA 769 Glu-755-StopGATCTCATGTTAAGTGGA G AAAGGGTTTTGCAAACTGAAAGA GAA to TAATCTGTAGAGAGTAGCAGTATTTCATTGGTACCTGGTATACCAGGTACCAATGAAATACTGCTACTCTCTACAGATCTTTC 770 AGTTTGCAAAACCCTTT CTCCACTTAACATGAGATCTTTGGGG TCTTCAGCATTATTAGACACTTTAACTGTTTCTAG TAAGTGGA GAAAGGGTT 771 AACCCTTT C TCCACTTA 772 Breast CancerTCATGTTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTG 773 Ser-770-StopTAGAGAGTAGCAGTATTT C ATTGGTACCTGGTACTGATTATG TCA to TAAGCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCACGTGCTAACTTCCAGTAACGAGATACTTTCCTGAGTGCCATAA 774 TCAGTACCAGGTACCAAT GAAATACTGCTACTCTCTACAGAT CTTTCAGTTTGCAAAACCCTTTCTCCACTTAACATGA CAGTATTT CATTGGTAC 775 GTACCAAT G AAATACTG 776 Breast CancerTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTGTAGAGA 777 Val-772-AlaGTAGCAGTATTTCATTGG T ACCTGGTACTGATTATGGCACTC GTA to GCAAGGAAAGTATCTCGTTACTGGAAGTTAGCACTCTAGGCCTAGAGTGCTAACTTCCAGTAACGAGATACTTTCCTGAGTG 778 CCATAATCAGTACCAGGT ACCAATGAAATACTGCTACTCTCTA CAGATCTTTCAGTTTGCAAAACCCTTTCTCCACTTA TTCATTGG TACCTGGTA 779 TACCAGGT A CCAATGAA 780 Breast CancerACTGAAAGATCTGTAGAGAGTAGCAGTATTTCATTGGTACCT 781 Gln-780-StopGGTACTGATTATGGCACT C AGGAAAGTATCTCGTTACTGGAA GAG to TAGGTTAGCACTCTAGGGAAGGCAAAAACAGAACCAAATATATTTGGTTCTGTTTTTGCCTTCCCTAGAGTGCTAACTTCCAG 782 TAACGAGATACTTTCCT GAGTGCCATAATCAGTACCAGGTAC CAATGAAATACTGCTACTCTCTACAGATCTTTCAGT ATGGCACT CAGGAAAGT 783 ACTTTCCT G AGTGCCAT 784 Breast CancerTATGGCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCACT 785 Glu-797-StopCTAGGGAAGGCAAAAACA G AACCAAATAAATGTGTGAGTCAG GAA to TAATGTGCAGCATTTGAAAACCCCAAGGGACTAATTCATGCATGAATTAGTCCCTTGGGGTTTTCAAATGCTGCACACTGAC 786 TCACACATTTATTTGGTT CTGTTTTTGCCTTCCCTAGAGTGCT AACTTCCAGTAACGAGATACTTTCCTGAGTGCCATA CAAAAACA GAACCAAAT 787 ATTTGGTT C TGTTTTTG 788 Breast CancerAAATGTGTGAGTCAGTGTGCAGCATTTGAAAACCCCAAGGGA 789 Lys-820-GluCTAATTCATGGTTGTTCC A AAGATAATAGAAATGACACAGAAG AAA to GAAGCTTTAAGTATCCATTGGGACATGAAGTTAACCACATGTGGTTAACTTCATGTCCCAATGGATACTTAAAGCCTTCTGT 790 GTCATTTCTATTATCTT TGGAACAACCATGAATTAGTCCCTTG GGGTTTTCAAATGCTGCACACTGACTCACACATTT GTTGTTCC AAAGATAAT 791 ATTATCTT T GGAACAAC 792 Breast CancerCAGCATTTGAAAACCCCAAGGGACTAATTCATGGTTGTTCCA 793 Thr-826-LysAAGATAATAGAAATGACA C AGAAGGCTTTAAGTATCCATTGG ACA to AAAGACATGAAGTTAACCACAGTCGGGAAACAAGCATAGATCTATGCTTGTTTCCCGACTGTGGTTAACTTCATGTCCCAATG 794 GATACTTAAAGCCTTCT GTGTCATTTCTATTATCTTTGGAACA ACCATGAATTAGTCCCTTGGGGTTTTCAAATGCTG AAATGACA CAGAAGGCT 795 AGCCTTCT G TGTCATTT 796 Breast CancerGATAATAGAAATGACACAGAAGGCTTTAAGTATCCATTGGGA 797 Arg-841-TrpCATGAAGTTAACCACAGT C GGGAAACAAGCATAGAAATGGAA CGG to TGGGAAAGTGAACTTGATGCTCAGTATTTGCAGAATACATATGTATTCTGCAAATACTGAGCATCAAGTTCACTTTCTTCCAT 798 TTCTATGCTTGTTTCCC GACTGTGGTTAACTTCATGTCCCAAT GGATACTTAAAGCCTTCTGTGTCATTTCTATTATC ACCACAGT CGGGAAACA 799 TGTTTCCC G ACTGTGGT 800 Breast CancerAACTTGATGCTCAGTATTTGCAGAATACATTCAAGGTTTCAAA 801 Pro-871-LeuGCGCCAGTCATTTGCTC C GTTTTCAAATCCAGGAAATGCAGA CCG to CTGAGAGGAATGTGCAACATTCTCTGCCCACTCTGGGTCGACCCAGAGTGGGCAGAGAATGTTGCACATTCCTCTTCTGCA 802 TTTCCTGGATTTGAAAAC GGAGCAAATGACTGGCGCTTTGAA ACCTTGAATGTATTCTGCAAATACTGAGCATCAAGTT ATTTGCTC CGTTTTCAA 803 TTGAAAAC G GAGCAAAT 804 Breast CancerTTTCAAATCCAGGAAATGCAGAAGAGGAATGTGCAACATTCT 805 Leu-892-SerCTGCCCACTCTGGGTCCT T AAAGAAACAAAGTCCAAAAGTCA TTA to TCACTTTTGAATGTGAACAAAAGGAAGAAAATCAAGGAAATTTCCTTGATTTTCTTCCTTTTGTTCACATTCAAAAGTGACTTT 806 TGGACTTTGTTTCTTT AAGGACCCAGAGTGGGCAGAGAATGT TGCACATTCCTCTTCTGCATTTCCTGGATTTGAAA TGGGTCCT TAAAGAAAC 807 GTTTCTTT A AGGACCCA 808 Breast CancerCACTCTGGGTCCTTAAAGAAACAAAGTCCAAAAGTCACTTTTG 809 Glu-908-StopAATGTGAACAAAAGGAA G AAAATCAAGGAAAGAATGAGTCTA GAA to TAAATATCAAGCCTGTACAGACAGTTAATATCACTGCAGCTGCAGTGATATTAACTGTCTGTACAGGCTTGATATTAGACTC 810 ATTCTTTCCTTGATTTT CTTCCTTTTGTTCACATTCAAAAGTGA CTTTTGGACTTTGTTTCTTTAAGGACCCAGAGTG AAAAGGAA GAAAATCAA 811 TTGATTTT C TTCCTTTT 812 Breast CancerATAATGCCAAATGTAGTATCAAAGGAGGCTCTAGGTTTTGTCT 813 Gly-960-AspATCATCTCAGTTCAGAG G CAACGAAACTGGACTCATTACTCC GGC to GACAAATAAACATGGACTTTTACAAAACCCATATCGTATATACGATATGGGTTTTGTAAAAGTCCATGTTTTATTTGGAGTAA 814 TGAGTCCAGTTTCGTTG CCTCTGAACTGAGATGATAGACAAA ACCTAGAGCCTCCTTTGATACTACATTTGGCATTAT GTTCAGAG GCAACGAAA 815 TTTCGTTG C CTCTGAAC 816 Breast CancerATTTGTTAAAACTAAATGTAAGAAAAATCTGCTAGAGGAAAAC 817 Met-1008-IleTTTGAGGAACATTCAAT G TCACCTGAAAGAGAAATGGGAAAT ATG to ATAGAGAACATTCCAAGTACAGTGAGCACAATTAGCCGTACGGCTAATTGTGCTCACTGTACTTGGAATGTTCTCATTTCCC 818 ATTTCTCTTTCAGGTGA CATTGAATGTTCCTCAAAGTTTTCCT CTAGCAGATTTTTCTTACATTTAGTTTTAACAAAT CATTCAAT GTCACCTGA 819 TCAGGTGA C ATTGAATG 820 Breast CancerACTTTGAGGAACATTCAATGTCACCTGAAAGAGAAATGGGAA 821 Thr-1025-IleATGAGAACATTCCAAGTA C AGTGAGCACAATTAGCCGTAATA ACA to ATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTCAAGCTTGAGCTGGCTTCTTTAAAAACATTTTCTCTAATGTTATTACG 822 GCTAATTGTGCTCACT GTACTTGGAATGTTCTCATTTCCCATT TCTCTTTCAGGTGACATTGAATGTTCCTCAAAGT TCCAAGTA CAGTGAGCA 823 TGCTCACT G TACTTGGA 824 Breast CancerACATTCCAAGTACAGTGAGCACAATTAGCCGTAATAACATTAG 825 Glu-1038-GlyAGAAAATGTTTTTAAAG A AGCCAGCTCAAGCAATATTAATGAA GAA to GGAGTAGGTTCCAGTACTAATGAAGTGGGCTCCAGTATATACTGGAGCCCACTTCATTAGTACTGGAACCTACTTCATTAA 826 TATTGCTTGAGCTGGCT TCTTTAAAAACATTTTCTCTAATGTTA TTACGGCTAATTGTGCTCACTGTACTTGGAATGT TTTTAAAG AAGCCAGCT 827 AGCTGGCT T CTTTAAAA 828 Breast CancerCAAGTACAGTGAGCACAATTAGCCGTAATAACATTAGAGAAA 829 Ser-1040-AsnATGTTTTTAAAGAAGCCA G CTCAAGCAATATTAATGAAGTAGG AGC to AACTTCCAGTACTAATGAAGTGGGCTCCAGTATTAATGATCATTAATACTGGAGCCCACTTCATTAGTACTGGAACCTACTT 830 CATTAATATTGCTTGAG CTGGCTTCTTTAAAAACATTTTCTCTA ATGTTATTACGGCTAATTGTGCTCACTGTACTTG AGAAGCCA GCTCAAGCA 831 TGCTTGAG C TGGCTTCT 832 Breast CancerGCCGTAATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTC 833 Val-1047-AlaAAGCAATATTAATGAAG T AGGTTCCAGTACTAATGAAGTGGG GTA to GCACTCCAGTATTAATGAAATAGGTTCCAGTGATGAAAATTTTCATCACTGGAACCTATTTCATTAATACTGGAGCCCACTT 834 CATTAGTACTGGAACCT ACTTCATTAATATTGCTTGAGCTGGC TTCTTTAAAAACATTTTCTCTAATGTTATTACGGC TAATGAAG TAGGTTCCA 835 TGGAACCT A CTTCATTA 836 Breast CancerAAATAGGTTCCAGTGATGAAAACATTCAAGCAGAACTAGGTA 837 Leu-1080-StopGAAACAGAGGGCCAAAAT T GAATGCTATGCTTAGATTAGGGG TTG to TAGTTTTGCAACCTGAGGTCTATAAACAAAGTCTTCCTGGCCAGGAAGACTTTGTTTATAGACCTCAGGTTGCAAAACCCCT 838 AATCTAAGCATAGCATTC AATTTTGGCCCTCTGTTTCTACCTA GTTCTGCTTGAATGTTTTCATCACTGGAACCTATTT GCCAAAAT TGAATGCTA 839 TAGCATTC A ATTTTGGC 840 Breast CancerAAAACATTCAAGCAGAACTAGGTAGAAACAGAGGGCCAAAAT 841 Leu-1086-StopTGAATGCTATGCTTAGAT T AGGGGTTTTGCAACCTGAGGTCT TTA to TGAATAAACAAAGTCTTCCTGGAAGTAATTGTAAGCATCCGGATGCTTACAATTACTTCCAGGAAGACTTTGTTTATAGACCT 842 CAGGTTGCAAAACCCCT AATCTAAGCATAGCATTCAATTTTG GCCCTCTGTTTCTACCTAGTTCTGCTTGAATGTTTT GCTTAGAT TAGGGGTTT 843 AAACCCCT A ATCTAAGC 844 Breast CancerAGCAAGAATATGAAGAAGTAGTTCAGACTGTTAATACAGATTT 845 Ser-1130-StopCTCTCCATATCTGATTT C AGATAACTTAGAACAGCCTATGGGA TCA to TGAAGTAGTCATGCATCTCAGGTTTGTTCTGAGACACCGGTGTCTCAGAACAAACCTGAGATGCATGACTACTTCCCATA 846 GGCTGTTCTAAGTTATCT GAAATCAGATATGGAGAGAAATCT GTATTAACAGTCTGAACTACTTCTTCATATTCTTGCT TCTGATTT CAGATAACT 847 AGTTATCT G AAATCAGA 848 Breast CancerCTAGTTTTGCTGAAAATGACATTAAGGAAAGTTCTGCTGTTTT 849 Lys-1183-ArgTAGCAAAAGCGTCCAGA A AGGAGAGCTTAGCAGGAGTCCTA AAA to AGAGCCCTTTCACCCATACACATTTGGCTCAGGGTTACCGCGGTAACCCTGAGCCAAATGTGTATGGGTGAAAGGGCTAGG 850 ACTCCTGCTAAGCTCTCCT TTCTGGACGCTTTTGCTAAAAACA GCAGAACTTTCCTTAATGTCATTTTCAGCAAAACTAG CGTCCAGA AAGGAGAGC 851 GCTCTCCT T TCTGGACG 852 Breast CancerAGCGTCCAGAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTT 853 Gln-1200-StopCACCCATACACATTTGGCT C AGGGTTACCGAAGAGGGGCCA CAG to TAGAGAAATTAGAGTCCTCAGAAGAGAACTTATCTAGTGAGGCCTCACTAGATAAGTTCTCTTCTGAGGACTCTAATTTCTTGGC 854 CCCTCTTCGGTAACCCT GAGCCAAATGTGTATGGGTGAAAGG GCTAGGACTCCTGCTAAGCTCTCTTTTCTGGACGCT ATTTGGCT CAGGGTTAC 855 GTAACCCT G AGCCAAAT 856 Breast CancerAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTTCACCCATACA 857 Arg-1203-StopCATTTGGCTCAGGGTTAC C GAAGAGGGGCCAAGAAATTAGA CGA to TGAGTCCTCAGAAGAGAACTTATCTAGTGAGGATGAAGAGCGCTCTTCATCCTCACTAGATAAGTTCTCTTCTGAGGACTCTAA 858 TTTCTTGGCCCCTCTTC GGTAACCCTGAGCCAAATGTGTATG GGTGAAAGGGCTAGGACTCCTGCTAAGCTCTCCTTT AGGGTTAC CGAAGAGGG 859 CCCTCTTC G GTAACCCT 860 Breast CancerACCCATACACATTTGGCTCAGGGTTACCGAAGAGGGGCCAA 861 Glu-1214-StopGAAATTAGAGTCCTCAGAA G AGAACTTATCTAGTGAGGATGA GAG to TAGAGAGCTTCCCTGCTTCCAACACTTGTTATTTGGTAAAGCTTTACCAAATAACAAGTGTTGGAAGCAGGGAAGCTCTTCAT 862 CCTCACTAGATAAGTTCT CTTCTGAGGACTCTAATTTCTTGGC CCCTCTTCGGTAACCCTGAGCCAAATGTGTATGGGT CCTCAGAA GAGAACTTA 863 TAAGTTCT C TTCTGAGG 864 Breast CancerTCAGGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAG 865 Glu-1219-AspAAGAGAACTTATCTAGTGA G GATGAAGAGCTTCCCTGCTTCC GAG to GAGAACACTTGTTATTTGGTAAAGTAAACAATATACCTTCTAGAAGGTATATTGTTTACTTTACCAAATAACAAGTGTTGGAAG 866 CAGGGAAGCTCTTCATC CTCACTAGATAAGTTCTCTTCTGAG GACTCTAATTTCTTGGCCCCTCTTCGGTAACCCTGA TCTAGTGA GGATGAAGA 867 TCTTCATC C TCACTAGA 868 Breast CancerGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAGAAGA 869 Glu-1221-StopGAACTTATCTAGTGAGGAT G AAGAGCTTCCCTGCTTCCAACA GAA to TAACTTGTTATTTGGTAAAGTAAACAATATACCTTCTCAGTACTGAGAAGGTATATTGTTTACTTTACCAAATAACPAGTGTTG 870 GAAGCAGGGAAGCTCTT CATCCTCACTAGATAAGTTCTCTTC TGAGGACTCTAATTTCTTGGCCCCTCTTCGGTAACC GTGAGGAT GAAGAGCTT 871 AAGCTCTT C ATCCTCAC 872 Breast CancerTTATTTGGTAAAGTAAACAATATACCTTCTCAGTCTACTAGGC 873 Glu-1250-StopATAGCACCGTTGCTACC G AGTGTCTGTCTAAGAACACAGAGG GAG to TAGAGAATTTATTATCATTGAAGAATAGCTTAAATGACTAGTCATTTAAGCTATTCTTCAATGATAATAAATTCTCCTCTGTG 874 TTCTTAGACAGACACT CGGTAGCAACGGTGCTATGCCTAGTA GACTGAGAAGGTATATTGTTTACTTTACCAAATAA TTGCTACC GAGTGTCTG 875 CAGACACT C GGTAGCAA 876 Breast CancerCTAGGCATAGCACCGTTGCTACCGAGTGTCTGTCTAAGAACA 877 Ser-1262-StopCAGAGGAGAATTTATTAT C ATTGAAGAATAGCTTAAATGACTG TCA to TAACAGTAACCAGGTAATATTGGCAAAGGCATCTCAGGATCCTGAGATGCCTTTGCCAATATTACCTGGTTACTGCAGTCAT 878 TTAAGCTATTCTTCAAT GATAATAAATTCTCCTCTGTGTTCTTA GACAGACACTCGGTAGCAACGGTGCTATGCCTAG TTTATTAT CATTGAAGA 879 TCTTCAAT G ATAATAAA 880 Breast CancerTTATCATTGAAGAATAGCTTAAATGACTGCAGTAACCAGGTAA 881 Gln-1281-StopTATTGGCAAAGGCATCT C AGGAACATCACCTTAGTGAGGAAA CAG to TAGCAAAATGTTCTGCTAGCTTGTTTTCTTCACAGTGCATGCACTGTGAAGAAAACAAGCTAGCAGAACATTTTGTTTCCTC 882 ACTAAGGTGATGTTCCT GAGATGCCTTTGCCAATATTACCTG GTTACTGCAGTCATTTAAGCTATTCTTCAATGATAA AGGCATCT CAGGAACAT 883 ATGTTCCT G AGATGCCT 884 Breast CancerGCTAGCTTGTTTTCTTCACAGTGCAGTGAATTGGAAGACTTG 885 Gln-1313-StopACTGCAAATACAAACACC C AGGATCCTTTCTTGATTGGTTCTT CAG to TAGCCAAACAAATGAGGCATCAGTCTGAAAGCCAGGGAGCTCCCTGGCTTTCAGACTGATGCCTCATTTGTTTGGAAGAAC 886 CAATCAAGAAAGGATCCT GGGTGTTTGTATTTGCAGTCAAGT CTTCCAATTCACTGCACTGTGAAGAAAACAAGCTAGC CAAACACC CAGGATCCT 887 AGGATCCT G GGTGTTTG 888 Breast CancerTCACAGTGCAGTGAATTGGAAGACTTGACTGCAAATACAAAC 889 Ile-1318-ValACCCAGGATCCTTTCTTG A TTGGTTCTTCCAAACAAATGAGG ATT to GTTCATCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACATGTCACTCAGACCAACTCCCTGGCTTTCAGACTGATGCCTCA 890 TTTGTTTGGAAGAACCAA TCAAGAAAGGATCCTGGGTGTTTG TATTTGCAGTCAAGTCTTCCAATTCACTGCACTGTGA CTTTCTTG ATTGGTTCT 891 AGAACCAA T CAAGAAAG 892 Breast CancerTTGGAAGACTTGACTGCAAATACAAACACCCAGGATCCTTTC 893 Gln-1323-StopTTGATTGGTTCTTCCAAA C AAATGAGGCATCAGTCTGAAAGC CAA to TAACAGGGAGTTGGTCTGAGTGACAAGGAATTGGTTTCAGCTGAAACCAATTCCTTGTCACTCAGACCAACTCCCTGGCTTT 894 CAGACTGATGCCTCATTT GTTTGGAAGAACCAATCAAGAAAG GATCCTGGGTGTTTGTATTTGCAGTCAAGTCTTCCAA CTTCCAAA CAAATGAGG 895 CCTCATTT G TTTGGAAG 896 Breast CancerCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACAAGGAATT 897 Arg-1347-GlyGGTTTCAGATGATGAAGAA A GAGGAACGGGCTTGGAAGAAA AGA to GGAATAATCAAGAAGAGCAAAGCATGGATTCAAACTTAGGTATACCTAAGTTTGAATCCATGCTTTGCTCTTCTTGATTATTTTCT 898 TCCAAGCCCGTTCCTC TTTCTTCATCATCTGAAACCAATTCCT TGTCACTCAGACCAACTCCCTGGCTTTCAGACTG ATGAAGAA AGAGGAACG 899 CGTTCCTC T TTCTTCAT 900 Breast CancerGAAACAAGCGTCTCTGAAGACTGCTCAGGGCTATCCTCTCAG 901 Gln-1395-StopAGTGACATTTTAACCACT C AGGTAAAAAGCGTGTGTGTGTGT CAG to TAGGCACATGCGTGTGTGTGGTGTCCTTTGCATTCAGTAGCTACTGAATGCAAAGGACACCACACACACGCATGTGCACACA 902 CACACACGCTTTTTACCT GAGTGGTTAAAATGTCACTCTGAG AGGATAGCCCTGAGCAGTCTTCAGAGACGCTTGTTTC TAACCACT CAGGTAAAA 903 TTTTACCT G AGTGGTTA 904 Breast CancerTGGTGCCATTTATCGTTTTTGAAGCAGAGGGATACCATGCAA 905 Gln-1408-StopCATAACCTGATAAAGCTC C AGCAGGAAATGGCTGAACTAGAA CAG to TAGGCTGTGTTAGAACAGCATGGGAGCCAGCCTTCTAACATGTTAGAAGGCTGGCTCCCATGCTGTTCTAACACAGCTTCTA 906 GTTCAGCCATTTCCTGCT GGAGCTTTATCAGGTTATGTTGCAT GGTATCCCTCTGCTTCAAAAACGATAAATGGCACCA TAAAGCTC CAGCAGGAA 907 TTCCTGCT G GAGCTTTA 908 Breast CancerAGCCAGCCTTCTAACAGCTACCCTTCCATCATAAGTGACTCT 909 Arg-1443-GlyTCTGCCCTTGAGGACCTG C GAAATCCAGAACAAAGCACATCA CGA to GGAGAAAAAGGTGTGTATTGTTGGCCAAACACTGATATCTAGATATCAGTGTTTGGCCAACAATACACACCTTTTTCTGATGT 910 Arg-1443-StopGCTTTGTTCTGGATTTC G CAGGTCCTCAAGGGCAGAAGAGTC CGA to TGAACTTATGATGGAAGGGTAGCTGTTAGAAGGCTGGCT AGGACCTG C GAAATCCA 911 TGGATTTC GCAGGTCCT 912 Breast Cancer CAGAATAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTT913 Ser-1512-Ile GTTGATGTGGAGGAGCAA C AGCTGGAAGAGTCTGGGCCACA AGT to ATTCGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATCGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTG 914 GCCCAGACTCTTCCAGCT GTTGCTCCTCCACATCAACPACCT TAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTG AGGAGCAA CAGCTGGAA 915 TTCCAGCT G TTGCTCCT 916 Breast CancerATCTTTCTAGGTCATCCCCTTCTAAATGCCCATCATTAGATGA 917 Gln-1538-StopTAGGTGGTACATGCACA G TTGCTCTGGGAGTCTTCAGAATAG GAG to TAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTTGTACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCT 918 GAAGACTCCCAGAGCAA CTGTGCATGTACCACCTATCATCTA ATGATGGGCATTTAGAAGGGGATGACCTAGAAAGAT CATGCACA GTTGCTCTG 919 CAGAGCAA C TGTGCATG 920 Breast CancerCAGAATAGAAACTACCCATCTCAAGAGGAGCTCATTAAGGTT 921 Glu-1541-StopGTTGATGTGGAGGAGCAA C AGCTGGAAGAGTCTGGGCCACA GAG to TAGCGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATCGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAAATCGTGTG 922 GCCCAGACTCTTCCAGCT GTTGCTCCTCCACATCAACAACCT TAATGAGCTCCTCTTGAGATGGGTAGTTTCTATTCTG AGGAGCAA CAGCTGGAA 923 TTCCAGCT G TTGCTCCT 924 Breast CancerAACTACCCATCTCAAGAGGAGCTCATTAAGGTTGTTGATGTG 925 Thr-1561-IleGAGGAGCAACAGCTGGAA G AGTCTGGGCCACACGATTTGAC ACC to ATCGGAAACATCTTACTTGCCAAGGCAAGATCTAGGTAATATATTACCTAGATCTTGCCTTGGCAAGTAAGATGTTTCCGTCAA 926 ATCGTGTGGCCCAGACT CTTCCAGCTGTTGCTCCTCCACATC AACAACCTTAATGAGCTCCTCTTGAGATGGGTAGTT AGCTGGAA GAGTCTGGG 927 CCCAGACT C TTCCAGCT 928 Breast CancerTTTGTAATTCAACATTCATCGTTGTGTAAATTAAACTTCTCCCA 929 Tyr-1563-StopTTCCTTTCAGAGGGAA C CCCTTACCTGGAATCTGGAATCAGC TAC to TAGCTCTTCTCTGATGACCCTGAATCTGATCCTTCTGATCAGAAGGATCAGATTCAGGGTCATCAGAGAAGAGGCTGATT 930 CCAGATTCCAGGTAAGGG GTTCCCTCTGAAAGGAATGGGAG AAGTTTAATTTACACAACGATGAATGTTGAATTACAAA AGAGGGAA CCCCTTACC 931 GGTAAGGG G TTCCCTCT 932 Breast CancerCAACATTCATCGTTGTGTAAATTAAACTTCTCCCATTCCTTTC 933 Leu-1564-ProAGAGGGAACCCCTTACC T GGAATCTGGAATCAGCCTCTTCTC CTG to CCGTGATGACCCTGAATCTGATCCTTCTGAAGACAGAGCGCTCTGTCTTCAGAAGGATCAGATTCAGGGTCATCAGAGAAG 934 AGGCTGATTCCAGATTCC AGGTAAGGGGTTCCCTCTGAAAG GAATGGGAGAAGTTTAATTTACACAACGATGAATGTTG CCCTTACC TGGAATCTG 935 CAGATTCC A GGTAAGGG 936 Breast CancerGCCCCAGAGTCAGCTCGTGTTGGCAACATACCATCTTCAACC 937 Gln-1604-StopTCTGCATTGAAAGTTCCC C AATTGAAAGTTGCAGAATCTGCC CAA to TAACAGAGTCCAGCTGCTGCTCATACTACTGATACTGCTGCAGCAGTATCAGTAGTATGAGCAGCAGCTGGACTCTGGGCA 938 GATTCTGCAACTTTCAATT GGGGAACTTTCAATGCAGAGGTT GAAGATGGTATGTTGCCAACACGAGCTGACTCTGGGGC AAGTTCCC CAATTGAAA 939 TTTCAATT G GGGAACTT 940 Breast CancerGAGTCAGCTCGTGTTGGCAACATACCATCTTCAACCTCTGCA 941 Lys-1606-GluTTGAAAGTTCCCCAATTG A AAGTTGCAGAATCTGCCCAGAGT AAA to GAACCAGCTGCTGCTCATACTACTGATACTGCTGGGTATATATACCCAGCAGTATCAGTAGTATGAGCAGCAGCTGGACTCT 942 GGGCAGATTCTGCAACTT TCAATTGGGGAACTTTCAATGCAG AGGTTGAAGATGGTATGTTGCCAACACGAGCTGACTC CCCAATTG AAAGTTGCA 943 TGCAACTT T CAATTGGG 944 Breast CancerCAGAATCTGCCCAGAGTCCAGCTGCTGCTCATACTACTGATA 945 Met-1628-ThrCTGCTGGGTATAATGCAA T GGAAGAAAGTGTGAGCAGGGAG ATG to ACGAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACAATTGTTGACCCTTTCTGTTGAAGCTGTCAATTCTGGCTTCTCCC 946 TGCTCACACTTTCTTCC ATTGCATTATACCCAGCAGTATCAGT AGTATGAGCAGCAGCTGGACTCTGGGCAGATTCTG TAATGCAA TGGAAGAAA 947 TTTCTTCC A TTGCATTA 948 Breast CancerGCAGAATCTGCCCAGAGTCCAGCTGCTGCTCATACTACTGAT 949 Met-1628-ValACTGCTGGGTATAATGCA A TGGAAGAAAGTGTGAGCAGGGA ATG to GTGGAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACATGTTGACCCTTTCTGTTGAAGCTGTCAATTCTGGCTTCTCCCT 950 GCTCACACTTTCTTCCA TTGCATTATACCCAGCAGTATCAGTA GTATGAGCAGCAGCTGGACTCTGGGCAGATTCTGC ATAATGCA ATGGAAGAA 951 TTCTTCCA T TGCATTAT 952 Breast CancerCTCATACTACTGATACTGCTGGGTATAATGCAATGGAAGAAA 953 Pro-1637-LeuGTGTGAGCAGGGAGAAGC C AGAATTGACAGCTTCAACAGAA CCA to CTAAGGGTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCTAGGCCAGACACCACCATGGACATTCTTTTGTTGACCCTTTCT 954 GTTGAAGCTGTCAATTCT GGCTTCTCCCTGCTCACACTTTCTT CCATTGCATTATACCCAGCAGTATCAGTAGTATGAG GGAGAAGC CAGAATTGA 955 TCAATTCT G GCTTCTCC 956 Breast CancerGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAAAGGG 957 Met-1652-IleTCAACAAAAGAATGTCCAT G GTGGTGTCTGGCCTGACCCCAG ATG to ATAAAGAATTTGTGAGTGTATCCATATGTATCTCCCTAATGCATTAGGGAGATACATATGGATACACTCACAAATTCTTCTGG 958 GGTCAGGCCAGACACCAC CATGGACATTCTTTTGTTGACCCT TTCTGTTGAAGCTGTCAATTCTGGCTTCTCCCTGCTC ATGTCCAT GGTGGTGTC 959 GACACCAC C ATGGACAT 960 Breast CancerCACTTCCTGATTTTGTTTTCAACTTCTAATCCTTTGAGTGTTTT 961 Glu-1694-StopTCATTCTGCAGATGCT G AGTTTGTGTGTGAACGGACACTGAA GAG to TAGATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGCTACCCATTTTCCTCCCGCAATTCCTAGAAAATATTTCAGTGT 962 CCGTTCACACACAAACT CAGCATCTGCAGAATGAAAAACACT CAAAGGATTAGAAGTTGAAAACAAAATCAGGAAGTG CAGATGCT GAGTTTGTG 963 CACAAACT C AGCATCTG 964 Breast CancerGTGTTTTTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGA 965 Gly-1706-GluCACTGAATATTTTCTAG G AATTGCGGGAGGAAAATGGGTAG GGA to GAATTAGCTATTTCTGTAAGTATAATACTATTTCTCCCCTAGGGGAGAAATAGTATTATACTTACAGAAATAGCTAACTACCC 966 ATTTTCCTCCCGCAATT CCTAGAAAATATTTCAGTGTCCGTTC ACACACAAACTCAGCATCTGCAGAATGAAAAACAC TTTTCTAG GAATTGCGG 967 CCGCAATT C CTAGAAAA 968 Breast CancerTTCATTCTGCAGATGCTGAGTTTGTGTGTGAACGGACACTGA 969 Ala-1708-GluAATATTTTCTAGGAATTG C GGGAGGAAAATGGGTAGTTAGCT GCG to GAGATTTCTGTAAGTATAATACTATTTCTCCCCTCCTCCCGGGAGGAGGGGAGAAATAGTATTATACTTACAGAAATAGCTA 970 ACTACCCATTTTCCTCCC GCAATTCCTAGAAAATATTTCAGTG TCCGTTCACACACAAACTCAGCATCTGCAGAATGAA AGGAATTG CGGGAGGAA 971 TTCCTCCCGCAATTCCT 972 Breast CancerCTGAGTTTGTGTGTGAACGGACACTGAAAATATTTTCTAGGAAT 973 Val-1713-AlaTGCGGGAGGAAAATGGG T AGTTAGCTATTTCTGTAAGTATAA GTA to GCATACTATTTCTCCCCTCCTCCCTTTAACACCTCAGAATTCTGAGGTGTTAAAGGGAGGAGGGGAGAAATAGTATTATAC 974 TTACAGAAATAGCTAACT ACCCATTTTCCTCCCGCAATTCCTA GAAAATATTTCAGTGTCCGTTCACACACAAACTCAG AAAATGGG TAGTTAGCT 975 AGCTAACT A CCCATTTT 976 Breast CancerAACGGACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAAT 977 Trp-1718-StopGGGTAGTTAGCTATTTCT G TAAGTATAATACTATTTCTCCCCT TGG to TAGCCTCCCTTTAACACCTCAGAATTGCATTTTTACACCGGTGTAAAAATGCAATTCTGAGGTGTTAAAGGGAGGAGGGG 978 AGAAATAGTATTATACTTA CAGAAATAGCTAACTACCCATTTTC CTCCCGCAATTCCTAGAAAATATTTCAGTGTCCGTT CTATTTCT GTAAGTATA 979 TATACTTA C AGAAATAG 980 Breast CancerTTCTGCTGTATGTAACCTGTCTTTTCTATGATCTCTTTAGGGG 981 Glu-1725-StopTGACCCAGTCTATTAAA G AAAGAAAAATGCTGAATGAGGTAA GAA to TAAGTACTTGATGTTACAAACTAACCAGAGATATTCATTAATGAATATCTCTGGTTAGTTTGTAACATCAAGTACTTACCTC 982 ATTCAGCATTTTTCTTT CTTTAATAGACTGGGTCACCCCTAAA GAGATCATAGAAAAGACAGGTTACATACAGCAGAA CTATTAAA GAAAGAAAA 983 TTTTCTTT C TTTAATAG 984 Breast CancerTGTATGTAACCTGTCTTTTCTATGATCTCTTTAGGGGTGACCC 985 Lys-1727-StopAGTCTATTAAAGAAAGA A AAATGCTGAATGAGGTAAGTACTTG AAA to TAAATGTTACAAACTAACCAGAGATATTCATTCAGTCATGACTGAATGAATATCTCTGGTTAGTTTGTAACATCAAGTACT 986 TACCTCATTCAGCATTT TTCTTTCTTTAATAGACTGGGTCACC CCTAAAGAGATCATAGAAAAGACAGGTTACATACA AAGAAAGA AAAATGCTG 987 CAGCATTT T TCTTTCTT 988 Breast CancerTCTTTCAGCATGATTTTGAAGTCAGAGGAGATGTGGTCAATG 989 Pro-1749-ArgGAAGAAACCACCAAGGTC C AAAGCGAGCAAGAGAATCCCAG CCA to CGAGACAGAAAGGTAAAGCTCCCTCCCTCAAGTTGACAAAATTTTGTCAACTTGAGGGAGGGAGCTTTACCTTTCTGTCCTGG 990 GATTCTCTTGCTCGCTTT GGACCTTGGTGGTTTCTTCCATTGA CCACATCTCCTCTGACTTCAAAATCATGCTGAAAGA CCAAGGTC CAAAGCGAG 991 CTCGCTTT G GACCTTGG 992 Breast CancerCAGCATGATTTTGAAGTCAGAGGAGATGTGGTCAATGGAAGA 993 Arg-1751-StopAACCACCAAGGTCCAAAG C GAGCAAGAGAATCCCAGGACAG CGA to TGAAAAGGTAAAGCTCCCTCCCTCAAGTTGACAAAAATCTCGAGATTTTTGTCAACTTGAGGGAGGGAGCTTTACCTTTCTGT 994 CCTGGGATTCTCTTGCTC GCTTTGGACCTTGGTGGTTTCTTC CATTGACCACATCTCCTCTGACTTCAAAATCATGCTG GTCCAAAG CGAGCAAGA 995 TCTTGCTC G CTTTGGAC 996 Breast CancerGTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCC 997 Gln-1756-StopAAAGCGAGCAAGAGAATCC C AGGACAGAAAGGTAAAGCTCC GAG to TAGCTCCCTCAAGTTGACAAAAATCTCACCCCACCACTCTGTACAGAGTGGTGGGGTGAGATTTTTGTCAACTTGAGGGAGGG 998 AGCTTTACCTTTCTGTCCT GGGATTCTCTTGCTCGCTTTGGA CCTTGGTGGTTTCTTCCATTGACCACATCTCCTCTGAC GAGAATCC CAGGACAGA 999 TCTGTCCT G GGATTCTC 1000 Breast CancerCTCTCTTCTTCCAGATCTTCAGGGGGCTAGAAATCTGTTGCT 1001 Met-1775-ArgATGGGCCCTTCACCAACA T GCCCACAGGTAAGAGCCTGGGA ATG to AGGGAACCCCAGAGTTCCAGCACCAGCCTTTGTCTTACATATATGTAAGACAAAGGCTGGTGCTGGAACTCTGGGGTTCTCCC 1002 AGGCTCTTACCTGTGGGC ATGTTGGTGAAGGGCCCATAGCA ACAGATTTCTAGCCCCCTGAAGATCTGGAAGAAGAGAG CACCAACA TGCCCACAG 1003 CTGTGGGC A TGTTGGTG 1004 Breast CancerAGTATGCAGATTACTGCAGTGATTTTACATCTAAATGTCCATT 1005 Trp-1782-StopTTAGATCAACTGGAATG G ATGGTACAGCTGTGTGGTGCTTCT TGG to TGAGTGGTGAAGGAGCTTTCATCATTCACCCTTGGCACATGTGCCAAGGGTGAATGATGAAAGCTCCTTCACCACAGAAGC 1006 ACCACACAGCTGTACCAT CCATTCCAGTTGATCTAAAATGGA CATTTAGATGTAAAATCACTGCAGTAATCTGCATACT CTGGAATG GATGGTACA 1007 TGTACCAT C CATTCCAG 1008 Breast CancerATTACTGCAGTGATTTTACATCTAAATGTCCATTTTAGATCAAC 1009 Gln-1785-HisTGGAATGGATGGTACA G CTGTGTGGTGCTTCTGTGGTGAAG CAG to CATGAGCTTTCATCATTCACCCTTGGCACAGTAAGTATTAATACTTACTGTGCCAAGGGTGAATGATGAAAGCTCCTTCAC 1010 CACAGAAGCACCACACAG CTGTACCATCCATTCCAGTTGATC TAAAATGGACATTTAGATGTAAAATCACTGCAGTAAT ATGGTACA GCTGTGTGG 1011 CCACACAG C TGTACCAT 1012 Breast CancerGTCCATTTTAGATCAACTGGAATGGATGGTACAGCTGTGTGG 1013 Glu-1794-AspTGCTTCTGTGGTGAAGGA G CTTTCATCATTCACCCTTGGCAC GAG to GATAGTAAGTATTGGGTGCCCTGTCAGAGAGGGAGGACACGTGTCCTCCCTCTCTGACAGGGCACCCAATACTTACTGTGCC 1014 AAGGGTGAATGATGAAAG CTCCTTCACCACAGAAGCACCACA CAGCTGTACCATCCATTCCAGTTGATCTAAAATGGAC GTGAAGGA GCTTTCATC 1015 GATGAAAG C TCCTTCAC 1016 Breast CancerCTCTGCTTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGT 1017 Arg-1835-StopGAGGCACCTGTGGTGACC C GAGAGTGGGTGTTGGACAGTGT CGA to TGAAGCACTCTACCAGTGCCAGGAGCTGGACACCTACCTGATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAGTGCTACA 1018 CTGTCCAACACCCACTCTC GGGTCACCACAGGTGCCTCACA CATCTGCCCAATTGCTGGAGACAGAGAACACAAGCAGAG TGGTGACC CGAGAGTGG 1019 CCACTCTC G GGTCACCA 1020 Breast CancerTTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGTGAGGCA 1021 Trp-1837-ArgCCTGTGGTGACCCGAGAG T GGGTGTTGGACAGTGTAGCACT TGG to CGGCTACCAGTGCCAGGAGCTGGACACCTACCTGATACCCCGGGGTATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAGT 1022 GCTACACTGTCCAACACCC ACTCTCGGGTCACCACAGGTGC CTCACACATCTGCCCAATTGCTGGAGACAGAGAACACAA CCCGAGAG TGGGTGTTG 1023 CAACACCC A CTCTCGGG 1024 Breast CancerTGTGTTCTCTGTCTCCAGCAATTGGGCAGATGTGTGAGGCAC 1025 Trp-1837-StopCTGTGGTGACCCGAGAGT G GGTGTTGGACAGTGTAGCACTC TGG to TAGTACCAGTGCCAGGAGCTGGACACCTACCTGATACCCCATGGGGTATCAGGTAGGTGTCCAGCTCCTGGCACTGGTAGAG 1026 TGCTACACTGTCCAACACC CACTCTCGGGTCACCACAGGTG CCTCACACATCTGCCCAATTGCTGGAGACAGAGAACACA CCGAGAGT GGGTGTTGG 1027 CCAACACC C ACTCTCGG 1028

[0126] TABLE 15 BRCA2 Mutations and Genome-Correcting Oligos ClinicalPhenotype & SEQ ID Mutation Correcting Oligos NO: Breast cancerGTTAAAACTAAGGTGGGATTTTTTTTTTAAATAGATTTAGGAC 1029 PHE32LEUCAATAAGTCTTAATTGGTTTGAAGAACTTTCTTCAGAAGCTCC TTT to CTTACCCTATAATTCTGAACCTGCAGAAGAATCTGAACGTTCAGATTCTTCTGCAGGTTCAGAATTATAGGGTGGAGCTT 1030CTGAAGAAAGTTCTTCAAACCAATTAAGACTTATTGGTCCTAAATCTATTTAAAAAAAAAATCCCACCTTAGTTTTAAC TTAATTGGTTTGAAGAA 1031TTCTTCAAACCAATTAA 1032 Breast cancerTAGATTTAGGACCAATAAGTCTTAATTGGTTTGAAGAACTTTC 1033 TYR42CYSTTCAGAAGCTCCACCCTATAATTCTGAACCTGCAGAAGAATC TAT to TGTTGAACATAAAAACAACAATTACGAACCAAACCTATTAATAGGTTTGGTTCGTAATTGTTGTTTTTATGTTCAGATTCTTC 1034TGCAGGTTCAGAATTATAGGGTGGAGCTTCTGAAGAAAGTTCTTCAAACCAATTAAGACTTATTGGTCCTAAATCTA TCCACCCTATAATTCTG 1035CAGAATTATAGGGTGGA 1036 Breast cancerAAGAACTTTCTTCAGAAGCTCCACCCTATAATTCTGAACCTGC 1037 LYS53ARGAGAAGAATCTGAACATAAAAACAACAATTACGAACCAAACCTA AAA to AGATTTAAAACTCCACAAAGGAAACCATCTTATAATCATGATTATAAGATGGTTTCCTTTGTGGAGTTTTAAATAGGTTG 1038GTTCGTAATTGTTGTTTTTATGTTCAGATTCTTCTGCAGGTTCAGAATTATAGGGTGGAGCTTCTGAAGAAAGTTCTT TCAACATAAAAACAACA 1039TGTTGTTTTTATGTTCA 1040 Breast cancerCTATTTAAACTCCACAAAGGAAACCATCTTATAATCAGCTGG 1041 Phe81LeuCTTCAACTCCAATAATATTCAAAGAGCAAGGGCTGACTCTGC TTC to CTCCGCTGTACCAATCTCCTGTAAAAGAATTAGATAAATATTTATCTAATTCTTTTACAGGAGATTGGTACAGCGGCAGAGT 1042CAGCCCTTGCTCTTTGAATATTATTGGAGTTGAAGCCAGCTGATTATAAGATGGTTTCCTTTGTGGAGTTTTAAATAG CAATAATATTCAAAGAG 1043CTCTTTGAATATTATTG 1044 Breast cancerGTCAGACACCAAAACATATTTCTGAAAGTCTAGGAGCTGAGG 1045 TRP194TERMTGGATCCTGATATGTCTTGGTCAAGTTCTTTAGCTACACCACC TGG to TAGCACCCTTAGTTCTACTGTGCTCATAGGTAATAATAGCTATTATTACCTATGAGCACAGTAGAACTAAGGGTGGGTGGT 1046GTAGCTAAAGAACTTGACCAAGACATATCAGGATCCACCTCAGCTCCTAGACTTTCAGAAATATGTTTTGGTGTCTGAC TATGTCTTGGTCAAGTT 1047AACTTGACCAAGACATA 1048 Breast cancerCTGAAAGTCTAGGAGCTGAGGTGGATCCTGATATGTCTTGGT 1049 PRO201ARGCAAGTTCTTTAGCTACACCACCCACCCTTAGTTCTACTGTGCT CCA to CGACATAGGTAATAATAGCAAATGTGTATTTACAAGAAATTTCTTGTAAATACACATTTGCTATTATTACCTATGAGCACAGT 1050AGAACTAAGGGTGGGTGGTGTAGCTAAAGAACTTGACCAAGACATATCAGGATCCACCTCAGCTCCTAGACTTTCAG AGCTACACCACCCACCC 1051GGGTGGGTGGTGTAGCT 1052 Breast cancerACAATACACATAAATTTTTATCTTACAGTCAGAAATGAAGAAG 1053 Pro222SerCATCTGAAACTGTATTTCCTCATGATACTACTGCTGTAAGTAA CCT to TCTATATGACATTGATTAGACTGTTGAAATTGCTAACATGTTAGCAATTTCAACAGTCTAATCAATGTCATATTTACTTACA 1054GCAGTAGTATCATGAGGAATACAGTTTCAGATGCTTCTTCATTTCTGACTGTAAGATAAAAATTTATGTGTATTGT CTGTATTTCCTCATGAT 1055ATCATGAGGAAATACAG 1056 Breast cancerAATGGTCTCAACTAACCCTTTCAGGTCTAAATGGAGCCCAGA 1057 Leu-414-TermTGGAGAAAATACCCCTATTGCATATTTCTTCATGTGACCAAAA TTG to TAGTATTTCAGAAAAAGACCTATTAGACACAGAGAACAATTGTTCTCTGTGTCTAATAGGTCTTTTTCTGAAATATTTTGGTC 1058ACATGAAGAAATATGCAATAGGGGTATTTTCTCCATCTGGGCTCCATTTAGACCTGAAAGGGTTAGTTGAGACCATT ACCCCTATTGCATATTT 1059AAATATGCAATAGGGGT 1060 Breast cancer, maleAGCCTCTGAAAGTGGACTGGAAAATACATACTGTTTGCTCACA 1061 Cys554TrpGAAGGAGGACTCCTTATGTCCAAATTTAATTGATAATGGAAG TGT to TGGCTGGCCAGCCACCACCACACAGAATTCTGTAGCTTTGCAAAGCTACAGAATTCTGTGTGGTGGTGGCTGGCCAGCTTC 1062CATTATCAATTAAATTTGGACATAAGGAGTCCTCCTTCTGTGAGCAAACAGTATGTATTTCCAGTCCACTTTCAGAGGCT TCCTTATGTCCAAATTT 1063AAATTTGGACATAAGGA 1064 Breast cancerAACTCTACCATGGTTTTATATGGAGACACAGGTGATAAACAA 1065 Lys944TermGCAACCCAAGTGTCAATTAAAAAAGATTGGTTTATGTTCTTG AAA to TAACAGAGGAGAACAAAAATAGTGTAAAGCAGCATATAATTATATGCTGCTTTACACTATTTTTGTTCTCCTCTGCAAGAAC 1066ATAAACCAAATCTTTTTTAATTGACACTTGGGTTGCTTGTTTATCACCTGTGTCTCCATATAAAACCATGGTAGAGTT TGTCAATTAAAAAAGAT 1067ATCTTTTTTAATTGACA 1068 Breast cancer, maleATGACTACTGGCACTTTTGTTGAAGAATTACTGTTACA 1069 Glu 1320TermAGAGAAATACTGAAAATGAAGATAACAAATATACTGCTGCCAG GAA to TAATAGAAATTCTCATAACTTAGAATTTGATGGCAGTGCACTGCCATCAAATTCTAAGTTATGAGAATTTCTACTGGCAGC 1070AGTATATTTGTTATTTTCATTTTCAGTATTTCTCTTGTAATTTCAGTAATTTCTTCAACAAAAGTGCCAGTAGTCAT CTGAAAATGAAGATAAC 1071GTTATCTTCATTTTCAG 1072 Breast cancerCATGAAACAATTAAAAAAGTGAAAGACATATTTACAGACAGT 1073 Glu1876TermTCAGTAAAGTAATTAAGGAAAACAACGAGAATAAATCAAAAAT GAA to TAATTGCCAAACGAAAATTATGGCAGGTTGTTACGAGGCCTCGTAACAACCTGCCATAATTTTCGTTTGGCAAATTTTTGA 1074TTTATTCTCGTTGTTTTCCTTAATTATTTACTGAAACTGTCTGTAAATATGTCTCACTTTTTTAATTGTTTCATG TAATTAAGGAAAACAAC 1075 GTTGTTTCCTTAATTA1076 Breast cancer TGAAAGACATATTTACAGACAGTTTCAGTAAAGTAATTAAGGA 1077Ser1882Term AAACAACGAGAATTAAATCAAAAATTTGCCAAACGAAAATTATG TCA to TAAGCAGGTTGTTACGAGGCATTGGATGATTCAGAGGATCCTCTGAATCATCCAATGCCTCGTAACAACCTGCCATAATTT 1078TCGTTTGGCAAATTTTTGATTTATTCTCGTTGTTTCCTTAATTACTTTACTGAAACTGTCTGTAAATATGTCTTTCA GAATAAATCAAAAATTT 1079AAATTTTTGATTTATTC 1080 Breast cancerAACCAAAATATGTCTGGATTGGAGAAAGTTTCTAAAATATCAC 1081 Glu1953TermCTTGTGATGTTAGTTTGGAAACTTCAGATATATGTAAATGTAG GAA to TAATATAGGGAAGCTTCATAAGTCAGTCTCATCTGCAATTGCAGATGAGACTGACTTATGAAGCTTCCCTATACTACTTT 1082ACATATATCTGAAGTTTCCAAACTAACATCACAAGGTGATATTTTAGAAACTTTCTCCAATCCAGACATATTTTGGTT TTAGTTTGGAAACTTCA 1083TGAAGTTTCCAAACTAA 1084 Breast cancerTTAGTTTGGAAACTTCAGATATATGTAAATGTAGTATAGGGAA 1085 Ser1970TermGCTTCATAAGTCAGTCTCATCTGCAAATACTTGTGGGATTTTT TCA to TAAAGCACAGCAAGTGGAAAATCTGTCCAGGTATCAGATCTGATACCTGGACAGATTTTCCACTTGCTGTGCTAAAAATCC 1086CACAAGTATTTGCAGATGAGACTGACTTATGAAGCTCCCTATACTACTTTACATATATCTGAAGTTTCCAAAACTAA GTCAGTCTCATCTGCAA 1087TTGCAGATGAGACTGAC 1088 Breast cancerAAGTCAGTCTCATCTGCAAATACTTGTGGGATTTTTAGCACAG 1089 Gln 1987TermCAAGTGGAAAATCTGTCCAGGTATCAGATGCTTCATTACTTT CAG to TAGCGCAAGACAAGTGTTTTCTGAAATAGAAGATAGTATACTATCTTCTATTTCAGAAAACACTTGTCTTGCGTTTTGTAAT 1090GAAGCATCTGATACCTGGACAGATTTTCCACTTGCTGTGCTAAAAATCCCACAAGTATTTGCAGATGAGACTGACTT AATCTGTCCAGGTATCA 1091TGATACCTGGACAGATT 1092 Breast cancerAAAATAAGATTAATGACAATGAGATTCATCAGTTTAACAAAAA 1093 Ala2466ValCAACTCCAATCAAGCAGCAGCTGTAACTTTCACAAAGTGTGA GCA to GTAAGAAGAACCTTTAGGTATTGTATGACAATTTGTGTGCACACAAATTGTCATACAATACCTAAAGGTTCTTCTTCACACT 1094TTGTGAAAGTTACAGCTGCTGCTTGATTGGAGTTGTTTTTGTTAAACTGATGAATCTCATTGTCATTAATCTTATTTT TCAAGCAGCAGCTGTAA 1095TTACAGCTGCTGCTTGA 1096 Breast cancerAGGCAACGCGTCTTTCCACAGCCAGGCAGTCTGTATCTTGCA 1097 Arg2520TermAAAACATCCACTCTGCCTCGAATCTCTCTGAAAGCAGCAGTA CGA to TGAGGAGGCCAAGTCCCCTCTGCGTGTCCTCATAAACAGGCCTGTTTATGAGGACACGCAGAGGGGACTTGGCCTCCTACT 1098GCTGCTTTCAGAGAGATTCGAGGCAGAGTGGATGTTTTTGCAAGATACAGACTGCCTGGCTGTGGAAAGACGCGTTGCCT CTCTGCCTCGAATCTCT 1099AGAGATTCGAGGCAGAG 1100 Breast cancerATTTCATTGAGCGCAAATATATCTGAAACTTCTAGCAATAAAA 1101 Gln2714TermCTAGTAGTGCAGATACCCAAAAAGTGGCCATTATTGAACTTA CAA to TAACAGATGGGTGGTATGCTGTTAAGGCCCAGTTAGATCGATCTAACTGGGCCTTAACAGCATACCACCCATCTGTAAGTT 1102CAATAATGGCCACTTTTTGGGTATCTGCACTACTAGTTTTATTGCTAGAAGTTTCAGATATATTTGCGCTCAATGAAAT CAGATACCCAAAAAGTG 1103CACTTTTTGGGTATCTG 1104 Breast cancerCAGAACTGGTGGGCTCTCCTGATGCCTGTACACCTCTTGAAG 1105 Leu2776TermCCCCAGAATCTCTTATGTTAAAGGTAAATTAATTTGCACTCTT TTA to TGAGGTAAAAATCAGTCATTGATTCAGTTAAATTCTAGATCTAGAATTTAACTGAATCAATGACTGATTTTTACCAAGAGTG 1106CAAATTAATTTACCTTTAACATAAGAGATTCTGGGGCTTCAAGAGGTGTACAGGCATCAGGAGAGCCCACCAGTTCTG TCTTATGTTAAAGATTT 1107AAATCTTTAACATAAGA 1108 Breast cancerCCTTTTGTTTTCTTAGAAAACACAACAAAACCATATTTACCATC 1109 Gln2893TermACGTGCACTAACAAGACAGCAAGTTCGTGCTTTGCAAGATGG CAG to TAGTGCAGAGCTTTATGAAGCAGTGAAGAATGCAGCAGCTGCTGCATTCTTCACTGCTTCATAAAGCTCTGCACCATCTTG 1110CAAAGCACGAACTTGCTGTCTTGTTAGTGCACGTGATGGTAAATATGGTTTTGTTGTGTTTTCTAAGAAAACAAAAGG TAACAAGACAGCAAGTT 1111AACTTGCTGTCTTGTTA 1112 Breast cancerAATCACAGGCAAATGTTGAATGATAAGAAACAAGCTCAGATC 1113 Ala2951CAGTTGGAAATTAGGAAGGCCATGGAATCTGCTGAACAAAAG GCC to ACCGAACAAGGTTTATCCAGGGATGTCACAACCGTGTGGATCCACACGGTTGTGACATCCCTTGATAAACCTTGTTCCTTTTG 1114TTCAGCAGATTCCATGGCCTTCCTAATTTCCAACTGGATCTGAGCTTGTTTCTTATCATTCAACATTTGCCTGTGATT TTAGGAAGGCCATGGAA 1115TTCCATGGCCTTCCTAA 1116 Breast cancerACAATTTACTGGCAATAAAGTTTTGGATAGACCTTAATGAGGATT 1117 Met3118ThrCATTATTAAGCCTCATATGTTAATTGCTGCAAGCAACCTCCAG ATG to ACGTGGCGACCAGAATCCAAATCAGGCCTTCTTACTTTAAGGTAAGAAGGCCTGATTTGGATTCTGGTCGCCACTGGAG 1118GTTGCTTGCAGCAATTAACATATGAGGCTTAATAATGTCCTCATTAAGGTCTATCCAAAACTTTATTGCCAGTAAATTGT GCCTCATATGTTAATTG 1119CAATTAACATATGAGGC 1120 Breast cancerGACTGAAACGACGTTGTACTACATCTCTGATCAAAGAACAGG 1121 Thr3401 MetGAGTTCCCAGGCCAGTACGGAAGAATGTGAGAAAAATAAGC ACG to ATGGGACACAATTACAACTAAAAAATATATCTAAGCATTAATGCTTAGATATATTTTTAGTTGTAATTGTGTCCTGCTTATT 1122TTTCTCACATTTTTCCGTACTGGCCTGGGAACTCTCCTGTTCTTTGATCAGAGATGTAGTACAACGTCGTTTCAGTC GGCCAGTACGGAAGAAT 1123ATTCTTCCGTACTGGCC 1124 Breast cancerTAAAGAACAGGAGAGTTCCCAGGCCAGTACGGAAGAATGTGA 1125 lle3412ValGAAAAATAAGCAGGACACAATTACAATTACAACTAAAAAATATATCTAA ATT to GTTGCATTTGCAAAGGCGACAATAAATTATTGACGCTTAATTAAGCGTCAATAATTTATTGTCGCCTTTGCAAATGCTTAGAT 1126ATATTTTTTAGTTGTAATTGTGTCCTGCTTATTTTTCTCACATTCTTCCGTACTGGCCTGGGAACTCTCCTGTTCTTT AGGACACAATTACAACT 1127AGTTGTAATTGTGTCCT 1128

EXAMPLE 9 Cystic Fibrosis—CFTR

[0127] Cystic fibrosis is a lethal disease affecting approximately onein 2,500 live Caucasian births and is the most common autosomalrecessive disease in Caucasians. Patients with this disease have reducedchloride ion permeability in the secretory and absorptive cells oforgans with epithelial cell linings, including the airways, pancreas,intestine, sweat glands and male genital tract This, in turn, reducesthe transport of water across the epithelia. The lungs and the GI tractare the predominant organ systems affected in this disease and thepathology is characterized by blocking of the respiratory and GI tractswith viscous mucus. The chloride impermeability in affected tissues isdue to mutations in a specific chloride channel, the cystic fibrosistransmembrane conductance regulator protein (CFTR), which preventsnormal passage of chloride ions through the cell membrane (Welsh et al.,Neuron, 8:821-829 (1992)). Damage to the lungs due to mucus blockage,frequent bacterial infections and inflammation is the primary cause ofmorbidity and mortality in CF patients and, although maintenance therapyhas improved the quality of patients' lives, the median age at death isstill only around 30 years. There is no effective treatment for thedisease, and therapeutic research is focused on gene therapy usingexogenous transgenes in viral vectors and/or activating the defective orother chloride channels in the cell membrane to normalize chloridepermeability (Tizzano et al., J. Pediat, 120:337-349 (1992)). However,the death of a teenage patient treated with an adenovirus vectorcarrying an exogenous CFTR gene in clinical trials in the late 1990'shas impacted this area of research.

[0128] The oligonucleotides of the invention for correction of the CFTRgene are attached as a table. TABLE 16 CFTR Mutations andGenome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation CorrectingOligos NO: Cystic fibrosis AAGGATACAGACAGCGCCTGGAATTGTCAGACATATACCAAA1129 Ala46Asp TCCCTTCTGTTGATTCTGCTGACAATCTATCTGAAAAATTGGA GCT to GATAGGTATGTTCATGTACATTGTTTAGTTGAAGAGAGCTCTCTTCAACTAAACTAATGTACATGAACATACCTTTCCAATTT 1130TTCAGATAGATTGTCAGCAGAATCAACAGAAGGGATTTGGTATATGTCTGACAATTCCAGGCGCTGTCTGTATCCTT TGATTCTGCTGACAATC 1131GATTGTCAGCAGAATCA 1132 Cystic fibrosisAGCGCCTGGAATTGTCAGACATATACCAAATCCCTTCTGTTG 1133 Ser50TyrATTCTGCTGACAATCTATCTGATTAAAATTGGAAAGGTATGTTCA TCT to TATTGTACATTGTTTAGTTGAAGAGAGAAATTCATATTATAATATGAATTTCTCTCTTCAACTAAACAATGTACATGAACATA 1134CCTTTCCAATTTTTCAGATAGATTGTCAGCAGAATCAACAGAAGGGATTTGGTATATGTCTGACAATTCCAGGCGCT CAATCTATCTGAAAAAT 1135ATTTTTCAGATAGATTG 1136 Congenital absence ofAGGACAACTAAAATATTTGCACATGCAACTTATTGGTCCCACT 1137 vas deferensTTTTATTCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAA Glu56LysGAAAAATCCTAAACTCATTAATGCCCTTCGGCGAT GAA-AAAATCGCCGAAGGGCATTAATGAGTTTAGGA1TTTTCTTTGAAGCTT 1138CAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACCAATAAGTTGCATGTGCAAATATTTTAGTTGTCCT TTTGCAGAGAATGGGAT 1139ATCCCATTCTCTGCAAA 1140 Cystic fibrosisAGGACAACTPAAATATTTGCACATGCAACTTATTGGTCCCACT 1141 Trp57GlyTTTTATTCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAA TGG to GGGGAAAAATCCTAAACTCATTAATGCCCTTCGGCGATATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGC 1142CAGCTCTCTATCCCATTCTCTGAAAAGAATAAAAAGTGGGACCAATAAGTTGCATGTGCAAATATTTTAGTTGTCCT TTTGCAGAGAATGGGAT 1143ATCCCATTCTCTGCAAA 1144 Cystic fibrosisAACTAAAATATTTGCACATGCAACTTATTGGTCCCACTTTTTAT 1145 Trp57TermTCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAA TGG to TGAATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTT 1146GAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACCAATAAGTTGCATGTGCAAATATTTTAGTT AGAGAATGGGATAGAGA 1147TCTCTATCCCATTCTCT 1148 Congenital absence ofACTAAAATATTTGCACATGCAACTTATTGGTCCCACTTTTTATT 1149 vas deferensCTTTTGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAA Asp58AsnTCCTAAACTCNTAATGCCCTTCGGCGATGTTTTT GAT to AATAGAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTT 1150TGAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACCAATAAGTTGCATGTGCAAATATTTTAGT GAGAATGGGATAGAGAG 1151CTCTCTATCCCATTCTC 1152 Cystic fibrosisATATTTGCACATGCAACTTATTGGTCCCACTTTTTATTCTTTTG 1153 Glu60TermCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAfiAAATCCTAA GAG to TAGACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGATCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGAT 1154TTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACCAATAAGTTGCATGTGCAAATAT GGGATAGAGAGCTGGCT 1155AGCCAGCTCTCTATCCC 1156 Cystic fibrosisGGTCCCACTTTTTATTCTTTTGCAGAGAATGGGATAGAGAGC 1157 Pro67LeuTGGCTTCAAAGAAAAATCCTAAACTCATTAATGCCCTTCGGC CCT to CTTGATGTTTTCTGGAGATT1ATGTTCTATGGAATCTTAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAA 1158GGGCATTAATGAGTTTAGGATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCTGCAAAAGAATAAAAAGTGGGACC GAAAAATCCTAAACTCA 1159TGAGTTAGGATTTTTC 1160 Cystic fibrosisTGCAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCT 1161 Arg74TrpAGCTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTA CGG to TGGTGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCT 1162CCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCTGCA ATGCCCTTCGGCGATGT 1163ACATCGCCGAAGGGCAT 1164 Congenital absence ofGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAAC 1165 vas deferensTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTT ARG75GLNCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTC CGA to CAAGAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAA 1166ATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTC CCTTCGGCGATGTTTTT 1167AGAACATCGCCGAAGG 1168 Cystic fibrosisGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAAC 1169 Arg75LeuTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTT CGA to CTACTATGGAATCTTTTTATATTTGGGGTAAGGATCTCGAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAA 1170ATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTC CCTTCGGCGATGTTTTT 1171AGAACATCGCCGAAGG 1172 Cystic fibrosisAGAGAATGGGATAGAGAGCTGGCTTCAAAGAAAAATCCTAAA 1173 Arg75TermCTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGT CGA to TGATCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAA 1174TCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTTTCTTTGAAGCCAGCTCTCTATCCCATTCTCT CCCTTCGGCGATGTTTT 1175AGACATCGCCGAAGGG 1176 Cystic fibrosisAGATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTG 1177 Gly85GluGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGTAAGG GGA to GAAATCTCATTTGTACATTCATTATGTATCACATAACTAGTTATGTGATACATAATGAATGTACAAATGAGATCCTTACCC 1178CTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTT GTTCTATGGAATCTTTT 1179AGAGATTCCATAGAAC 1180 Cystic fibrosisAGATCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTG 1181 Gly85ValGAGATTTATGTTCTATGGAATCTTTTTATATTTAGGGGTAAGG GGA to GTAATCTCATTTGTACATTCATTATGTATCACATAACTAGTTATGTGATACATAATGAATGTACAAATGAGATCCTTACCC 1182CTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGGATTTT GTTCTATGGAATCTTTT 1183AAAAGATTCCATAGAAC 1184 Cystic fibrosisAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT 1185 Leu88SerGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTCATTT TTA to TCAGTACATTCATTATGTATCACATAACTATATGCATTAATGCATATAGTTATGTGATACATAATGAATGTACPAATGAGATT 1186TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT AATCTTTTTATATTTAG 1187CTAAATATAAAAAGATT 1188 Cystic fibrosisCCTAAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGAT 1189 Phe87LeuTTATGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTC TTT to CTTATTTGTACATTCATTATGTATCACATAACTATATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGATCCT 1190TACCCCTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTTTAGG ATGGAATCTTTTTATAT 1191ATATAAAAAGATTCCAT 1192 Cystic fibrosisAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATT 1193 Leu88TermGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTCATTT TTA to TGAGTACATTCATTATGTATCACATAACTATATGCATTAATGCATATAGTTATGTGATACATAATGAATGTACAATTTGAGA 1194TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATTCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT AATCTTTTTATATTTAG 1195CTAAATATAAAAAGATT 1196 Cystic fibrosisAACTCATTAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTAT 1197 Leu88TermGTTCTATGGAATCTTTTTATATTTAGGGGTAAGGATCTCATTT TTA to TAAGTACATTCATTATGTATCACATAACTATATGCATTAATGCATATAGTTATGTGATACATAATGAATGTACAAATGAGA 1198TCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAAGGGCATTAATGAGTT AATCTTTTTATATTTAG 1199CTAAATATAAAAAGATT 1200 Cystic fibrosisAATGCCCTTCGGCGATGTTTTTTCTGGAGATTTATGTTCTATG 1201 Gly91ArgGAATCTTTTTATATTTAGGGGTAAGGATCTCATTTGTACATTC GGG to AGGTTATGTATCACATAACTATATGCATTTTTGTGATATCACAAAAATGCATATAGTTATGTGATACATAATGAATGTAC 1202AGTGAGATCCTTACCCCTAAATATAAAAAGATTCCATAGAACATAAATCTCCAGAAAAAACATCGCCGAAGGGCATT TATATTTAGGGGTAAGG 1203CCTTACCCCTAAATATA 1204 Cystic fibrosisAATAAATGAAATTTAATTTCTCTGTTTTTCCCCTTTTGTAGGAA 1205 Gln98ArgGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAATCATA CAG to CGGGCTTCCTATGACCCGGATAACAAGGAGGAACGCTCGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATT 1206CTTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAGAGGGGAAAAACAGAGAAATTAAATTTCATTTATT AGCAGTACAGCCTCTCT 1207AGAGAGGCTGTACTGCT 1208 Cystic fibrosisAAATAAATGAAATTTAATTTCTCTGTTTTTCCCCTTTTGTAGGA 1209 Gln98TermAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAATCAT CAG-TAGAGCTTCCTATGACCCGGATAACAAGGAGGAACGCTAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTC 1210TTCCCAGTAAGAGAGGCTGTACTGCTTGGTGACTTCCTACAAAAGGGGAAAAACAGAGAAATTAAATTTCATTTATTT AAGCAGTACAGCCTCTC 1211GAGAGGCTGTACTGCTT 1212 Cystic fibrosisCCCTTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTAC 1213 Ser108PheTGGGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGG TCC to TTCACGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCC 1214TTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAAAAGGG CATAGCTTCCTATGACC 1215GGTCATAGGAAGCTATG 1216 Cystic fibrosisTTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGG 1217 Tyr109CysGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGAAC TAT to TGTGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTCC 1218TCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAAAA AGCTTCCTATGACCCGG 1219CCGGGTCATAGGAAGCT 1220 Cystic fibrosisTTTGTAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGA 1221 Asp110HisGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGAACGC GAC to CACTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTCGAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTT 1222CCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCTACAA CTTCCTATGACCCGGAT 1223ATCCGGGTCATAGGAAG 1224 Congenital absence ofAGGAAGTCACCAAAGCAGTACAGCCTCTCTTACTGGGAAGAA 1225 vas deferensTTCATAGCTTCCTATGACCCGGATAACAAGGAGGAACGCTCTA Pro111LeuTCGCGATTTATCTAGGCATAGGCTTATGCCTTCTCTT CCG to CTGAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAG 1126CGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTACTGCTTTGGTGACTTCCT CTATGACCCGGATAACA 1227TGTTATCCGGGTCATAG 1228 Cystic fibrosisGTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGAC 1229 Arg117CysCCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGC CGC to TGCATAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCTA 1230GATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTAC AGGAGGAACGCTCTATC 1231GATAGAGCGTTCCTCCT 1232 Cystic fibrosisTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC 1233 Arg117HisCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCA CGC to CACTAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCTAGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT 1234AGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA GGAGGAACGCTCTATCG 1235CGATAGAGCGTTCCTCC 1236 Cystic fibrosisTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC 1237 Arg117LeuCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCA CGC to CTCTAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCTAGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT 1238AGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA GGAGGAACGCTCTATCG 1239CGATAGAGCGTTCCTCC 1240 Cystic fibrosisTACAGCCTCTCTTACTGGGAAGAATCATAGCTTCCTATGACC 1241 Arg117ProCGGATAACAAGGAGGAACGCTCTATCGCGATTTATCTAGGCA CGC to CCCTAGGCTTATGCCTTCTCTTTATTGTGAGGACACTGCTAGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCTATGCCT 1242AGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAGAGGCTGTA GGAGGAACGCTCTATCG 1243CGATAGAGCGTTCCTCC 1244 Cystic fibrosisCTCTTACTGGGAAGAATCATAGCTTCCTATGACCCGGATAAC 1245 Ala120ThrAGGAGGAACGCTCTATCGCGATTTATCTAGGCATAGGCTTA GCG-ACGTGCCTTCTCTTTATTGTGAGGACACTGCTCCTACACCGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGCATAAG 1246CCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCCAGTAAGAG GCTCTATCGCGATTTAT 1247ATAAATCGCGATAGAGC 1248 Cystic fibrosisGGGAAGAATCATAGCTTCCTATGACCCGGATAACAAGGAGGA 1249 Tyr122TermACGCTCTATCGCGATTTATCTAGGCATAGGCTTATGCCTTCT TAT to TAACTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTAATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAA 1250GGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTATGATTCTTCCC GCGATTTATCTAGGCAT 1251ATGCCTAGATAAATCGC 1252 Cystic fibrosisTAGCTTCCTATGACCCGGATAACAAGGAGGAACGCTCTATCG 1253 Gly126AspCGATTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGTGAG GGC-GACGACACTGCTCCTACACCCAGCCATTTTGGCCTTCATGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCAC 1254AATAAAGAGAAGGCATAAGCCTATGCCTAGATAAATCGCGATAGAGCGTTCCTCCTTGTTATCCGGGTCATAGGAAGCTA AGGCATAGGCTTATGCC 1255GGCATAAGCCATGCCT 1256 Cystic fibrosisTCGCGATTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGT 1257 His139ArgGAGGACACTGCTCCTACACCCAGCCATTTTTGGCCTTCATCA CAC to CGCCATTGGAATGCAGATGAGAATAGCTATGTTTAGTTTAAACTAAACATAGCTATTCTCATCTGCATTCCAATGTGATGAA 1258GGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCATGCCTAGATAAATCGCGA GCTCCTACACCCAGCCA 1259TGGCTGGGTGTAGGAGC 1260 Cystic fibrosisTTTATCTAGGCATAGGCTTATGCCTTCTCTTTATTGTGAGGAC 1261 Ala141AspACTGCTCCTACACCCAGCCATTTTTGGCCTTCATCACATTGG GCC to GACATGCAGATGAGAATAGCTATGTTTAGTTTGATTTATAAATCAAACTAAACATAGCTATTCTCATCTGCATTCCAATGT 1262GATGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGCATAAGCCATGCCTAGATAAA ACACCCAGCCATTTTTG 1263CAAAAATGGCTGGGTGT 1264 Cystic fibrosisGCCTTCTCTTTATTGTGAGGACACTGCTCCTACACCCAGCCA 1265 lle148ThrTTTTTGGCCTTCATCACATTGGAATGCAGATGAGAATAGCTAT ATT to ACTGTTTAGTTTGATTTATAAGAAGGTAATACTTCCTTGCAAGGAAGTATTACCTTCTTATAAATCAAACTAAACATAGCTA 1266TTCTCATCTGCATTCCAATGTGATGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAGGC TCATCACATTGGAATGC 1267GCATTCCAATGTGATGA 1268 Cystic fibrosisCTTCTCTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTT 1269 Gly149ArgTTGGCCTTCATCACATTGGAATGCAGATGAGAATAGCTATGTT GGA to AGATAGTTTGATTTATAAGAAGGTAATACTTCCTTGCATGCAAGGAAGTATTACCTTCTTATAAATCAAACTAAACATAGC 1270TATTCTCATCTGCATTCCAATGTGATGAAGGCCAAAAATATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAAGAGAAG ATCACATTGGAATGCAG 1271CTGCATTCCAATGTGAT 1272 Cystic fibrosisTTTATTGTGAGGACACTGCTCCTACACCCAGCCATTTTTGGC 1273 Gln151TermCTTCATCACATTGGAATGCAGATGAGAATAGCTATGTTTAGTT CAG to TAGTGATTTATAAGAAGGTAATACTTCCTTGCACAGGCCGGCCTGTGCAAGGAAGTATTACCTTCTTATAAATCAAACTT 1274CATAGCTATTCTCATCTGCATTCCAATGTGATGAAGGCCAAAAATGGCTGGGTGTAGGAGCAGTGTCCTCACAATAAA TTGGAATGCAGATGAGA 1275TCTCATCTGCATTCCAA 1276 Cystic fibrosisAATATATTTGTATTTTGTTTGTTGAAATTATCTAACTTTCCATTT 1277 Lys166GluTTCTTTTAGACTTTAAAGCTGTCAAGCCGTGTTCTAGATAAAA AAG-GAGTAAGTATTGGACAACTTGTTAGTCTCCTTTCCATGGAAAGGAGACTAACAAGTTGTCCAATACTTATTTTATCTAG 1278AACACGGCTTGACAGCTTTAAAGTCTAAAAGAAAAATGGAAAGTTAGATAATTTCAACAAACAAAATACAAATATATT AGACTTTAAAGCTGTCA 1279TGACAGCTTTAAAGTCT 1280 Cystic fibrosisTTATCTAACTTTCCATTTTTCTTTTAGACTTTAAAGCTGTCAAG 1281 lle175ValCCGTGTTCTAGATAAAATAAGTATTGGACAACTTGTTAGTCTC ATA-GTACTTTCCAACAACCTGAACAAATTTGATGAAGTATATACTTCATCAAATTTGTTCAGGTTGTTGGAAAGGAGACTAAC 1282AAGTTGTCCAATACTTATTTTATCTAGAACACGGCTTGACAGCTTTAAAGTCTAAAAGAAAAATGGAAAGTTAGATAA TAGATAAAATAAGTATT 1283AATACTTATTTTATCTA 1284 Cystic fibrosisTTTCCATTTTTCTTTTAGACTTTAAAGCTGTCAAGCCGTGTTCT 1285 Gly178ArgGATAAAATAAGTATTGGACAACTTGTTAGTCTCCTTTCCAAC GGA to AGAACCTGAACAAATTTGATGAAGTATGTACCTATTAATAGGTACATACTTCATCAAATTTGTTCAGGTTGTTGGAAAG 1286GAGACTAACAAGTTGTCCAATACTTATTTTATCTAGAACACGGCTTGACAGCTTTAAAGTCTAAAAGAAAAATGGAAA TAAGTATTGGACAACTT 1287AAGTTGTCCAATACTTA 1288 Cystic fibrosisAAGATACAATGACACCTGTTTTTGCTGTGCTTTTATTTTCCAG 1289 His199GlnGGACTTGCATTGGCACATTTCGTGTGGATCGCTCCTTTGCAA CAT to CAGGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGTTATAACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAA 1290AGGAGCGATCCACACGAAATGTGCCAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAAAACAGGTGTCATTGTATCTT TTGGCACATTTCGTGTG 1291CACACGAAATGTGCCAA 1292 Cystic fibrosisGGAAGATACAATGACACCTGTTTTTGCTGTGCTTTTATTTTCC 1293 His199TyrAGGGACTTGCATTGGCACATTTCGTGTGGATCGCTCCTTTGC CAT to TATAGTGGCACTCCTCATGGGGCTAATCTGGGAGTTGTACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAG 1294GAGCGATCCACACGAAATGTGCCAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAAAACAGGTGTCATTGTATCTTCC CATTGGCACATCGTG 1295CACGAAATGTGCCAATG 1296 Cystic fibrosisTGTTTTTGCTGTGCTTTTATTTTCCAGGGACTTGCATTGGCAC 1297 Pro205SerATTTCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGG CCT to TCTGGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCATG 1298AGGAGTGCCACTTGCAAAGGAGCGATCCACACGAAATGTGCCAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAAAACA GGATCGCTCCTTTGCAA 1299TTGCAAAGGAGCGATCC 1300 Cystic fibrosisTTTGCTGTGCTTTTATTTTCCAGGGACTTGCATTGGCACATTT 1301 Leu206TrpCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGGGGC TTG to TGGTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGTGGCCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCC 1302CATGAGGAGTGCCACTTGCAAAGGAGCGATCCACACGAAATGTGCCAATGCAAGTCCCTGGAAAATAAAAGCACAGCAAA CGCTCCTTTGCAAGTGG 1303CCACTTGCAAAGGAGCG 1304 Cystic fibrosisTTCGTGTGGATCGCTCCTTTGCAAGTGGCACTCCTCATGGG 1305 Gln220TermGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGTGGACT CAG to TAGTGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGGCGCCCAGCCGAAAAAGGGCAAGGACTATCAGGAAACCAAGT 1306CCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAGGAGCGATCCACACGAA AGTTGTTACAGGCGTCT 1307AGACGCCTGTAACAACT 1308 Cystic fibrosisCCTTTGCAAGTGGCACTCCTCATGGGGCTAATCTGGGAGTT 1309 Cys225ArgGTTACAGGCGTCTGCCTTCTGTGGACTTGGTTTCCTGATAGT TGT-CGTCCTTGCCCTTTTTCAGGCTGGGCTAGGGAGAATGATGATCATCATTCTCCCTAGCCCAGCCCTGAAAAGGGCAAGGACTA 1310TCAGGAAACCAAGTCCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCATGAGGAGTGCCACTTGCAAAGG CTGCCTTCTGTGGACTT 1311AAGTCCACAGAAGGCAG 1312 Cystic fibrosisTTGGGGCTAATCTGGGAGTTGTTACAGGCGTCTGCCTTCTGT 1313 Val232AspGGACTTGGTTTCCTGATAGTCCTTGCCCTTTTTCAGGCTGGG GTC to GACCTAGGGAGAATGATGATGAAGTACAGGTAGCAACCTATATAGGTTGCTACCTGTACTTCATCATCATTCTCCCTAGCCCA 1314GCCTGAAAAAGGGCAAGGACTATCAGGAAACCAAGTCCACAGAAGGCAGACGCCTGTAACAACTCCCAGATTAGCCCCA CCTGATAGTCCTTGCCC 1315GGGCAAGGACTATCAGG 1316 Cystic fibrosisGTTACAGGCGTCTGCCTTCTGTGGACTTGGTTTCCTGATAGT 1317 Gly239ArgCCTTGCCCTTTTTCAGGCTGGGCTAGGGAGAATGATGATGAA GGG to AGGGTACAGGTAGCAACCTATTTTCATAACTTGAAAGTTTAAAGCTTTCAAGTTATGAAAATAGGTTGCTACCTGTACTTCATC 1318ATCATTCTCCCTAGCCCAGCCGAAAAAGGGCAAGGACTATCAGGAAACCAAGTCCACAGAAGGCAGACGCCTGTAAC TTTCAGGCTGGGCTAGG 1319CCTAGCCCAGCCGAAA 1320

EXAMPLE 10 Cyclin-Dependent Kinase Inhibitor 2A—CDKN2A

[0129] The human CDKN2A gene was also designated MTS-1 for multipletumor suppressor-1 and has been implicated in multiple cancers,including, for example, malignant melanoma. Malignant melanoma is acutaneous neoplasm of melanocytes. Melanomas generally have features ofasymmetry, irregular border, variegated color, and diameter greater than6 mm. The precise cause of melanoma is unknown, but sunlight andheredity are risk factors. Melanoma has been increasing during the pastfew decades.

[0130] The CDKN2A gene has been found to be homozygously deleted at highfrequency in cell lines derived from tumors of lung, breast, brain,bone, skin, bladder, kidney, ovary, and lymphocyte. Melanoma cell linescarried at least one copy of CDKN2A in combination with a deletedallele. Melanoma cell lines that carried at least 1 copy of CDKN2Afrequently showed nonsense, missense, or frameshift mutations in thegene. Thus, CDKN2A may rival p53 (see Example 5) in the universality ofits involvement in tumorigenesis. The attached table discloses thecorrecting oligonucleotide base sequences for the CDKN2Aoligonucleotides of the invention. TABLE 17 CDKN2A Mutations andGenome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation CorrectingOligos NO: Melanoma GGGCGGCGGGGAGCAGCATGGAGCCGGCGGCGGGGAGCAG 1312Trp15Term CATGGAGCCTCGGCTGACTGGCTGGCCACGGCCGCGGCCC TGG-TAGGGGGTCGGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACCCCG 1322GGCCGCGGCCGTGGCCAGCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCGCCGGCTCCATGCTGCTCCCCGCCGCCC GGCTGACTGGCTGGCCA 1323TGGCCAGCCAGTCAGCC 1324 Melanoma CGGCGGGGAGCAGCATGGAGCCGGCGGCGGGGAGCAGCAT1325 Leu16Pro GGAGCCTCGGCTGACTGGCTGGCCACGGCCGCGGCCCGG CTG-CCGGGTCGGGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGG CGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACC 1326CCGGGCCGCGGCCGTGGCCAGCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCGCCGGCTCCATGCTGCTCCCCGCCG TGACTGGCTGGCCACGG 1327CCGTGGCCAGCCAGTCA 1328 Melanoma CGGCGGCGGGGAGCAGCATGGAGCCTCGGCTGACTGGCTG1329 Gly23Asp GCCACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGTGCGGG GGT-GATCGCTGCTGGAGGCGGGGGCGCTGCCCAACGCACCGAATAGCTATTCGGTGCGTTGGGCAGCGCCCCCCCGCCTCCAGCAGCGC 1330CCGCACCTCCTCTACCCGACCCCGGGCTTGCGGCCGTGGCCAGCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCGCCG GGCCCGGGGTCGGGTAG 1331CTACCCGACCCCGGGCC 1332 Melanoma CGGCGGGGAGCAGCATGGAGCCTCGGCTGACTGGCTGGCC1333 Arg24Pro ACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGTGCGGGCGC CGG-CCGTGCTGGAGGCGGGGGCGCTGCCCAACGCACCGAATAGTTATAACTATTCGGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGC 1334GCCCGCACCTCCTCTACCCGACCCCGGGCCGCGGCCGTGGCCAGCCAGTCAGCCGAAGGCTCCATGCTGCTCCCCGCCG CCGGGGTCGGGTAGAGG 1335CCTCTACCCGACCCCGG 1336 Melanoma CGGCTGACTGGCTGGCCACGGCCGCGGCCCGGGGTCGGGT1337 Leu32Pro AGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGGCGCTGCCC CTG-CCGAACGCACCGAATAGTTACGGTCGGAGGCCGATCCAGGTGGGCCCACCTGGATCGGCCTCCGACCGTAACTATTCGGTGCGTTG 1338GGCAGCGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACCCCGGGCCGCGGCCGTGGCCAGCCAGTCAGCCG GGCGCTGCTGGAGGCGG 1339CCGCCTCCAGCAGCGCC 1340 Melanoma GGCTGGCCACGGCCGCGGCCCGGGGTCGGGTAGAGGAGGT1341 Gly35Ala GCGGGCGCTGCTGGAGGCGGGGGCGCTGCCCAACGCACCG GGG-GCGAATAGTTACGGTCGGAGGCCGATCCAGGTGGGTAGAGGGTCGACCCTCTACCCACCTGGATCGGCCTCCGACCGTAACTATTC 1342GGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACCCGACCCCGGGCCGCGGCCGTGGCCAGCC GGAGGCGGGGGCGCTGC 1343GCAGCGCCCCCGCCTCC 1344 Melanoma GGTAGAGGAGGTGCGGGCGCTGCTGGAGGCGGGGGCGCTG1345 Tyr44Term CCCAACGCACCGAATAGTTACGGTCGGAGGCCGATCCAGGTG TACg-TAAGGTAGAGGGTCTGCAGCGGGAGCAGGGGATGGCGGGCGATCGCCCGCCATCCCCTGCTCCCGCTGCAGACCCTCTACCCAC 1346CTGGATCGGCCTCCGACCGTAACTATTCGGTGCGTTGGGCAGCGCCCCCGCCTCCAGCAGCGCCCGCACCTCCTCTACC AATAGTTACGGTCGGAG 1347CTCCGACCGTAACTATT 1348 MelanomaTCTCCCATACCTGCCCCCACCCTGGCTCTGACCACTCTGCTC 1349 Met53lleTCTCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGG ATGa-ATCAGCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCATGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCTCCG 1350CCACGCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAGCAGAGTGGTCAGAGCCAGGGTGGGGGCAGGTATGGGAGA GTCATGATGATGGGCAG 1351CTGCCCATCATCATGAC 1352 MelanomaCCCATACCTGCCCCCACCCTGGCTCTGACCACTCTGCTCTCT 1353 Met54lleCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGGAGC ATGg-ATTTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCAGACGTCTGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT 1354CCGCCACGCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAGCAGAGTGGTCAGAGCCAGGGTGGGGGCAGGTATGGG ATGATGATGGGCAGCGC 1355GCGCTGCCCATCATCAT 1356 MelanomaGCCGGCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGC 1357 Ser56lleAGGTCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTG AGC-ATCCTGCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCA 1358GCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGGCCGGC GATGGGCAGCGCCCGAG 1359CTCGGGCGCTGCCCATC 1360 MelanomaGGCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGG 1361 Ala57ValTCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTG GCC-GTCCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCA 1362GCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAACAGTAATGGTCAGAGCCAGGGTGGGGGCC GGGCAGCGCCCGAGTGG 1363CCACTCGGGCGCTGCCC 1364 MelanomaCCCCCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGGTC 1365 Arg58TermTGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGCT cCGA-TGACCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG 1366CAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTGGGGG GCAGCGCCCGAGTGGCG 1367CGCCACTCGGGCGCTGC 1368 MelanomaCACCCTGGCTCTGACCATTCTGTTCTCTCTGGCAGGTCATGAT 1369 Val59GlyGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGCTCCACG GTG-GGGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTG 1370GAGCAGCAGCAGCTCCGCCACTCGGGCGGTGCCCATCATCATGACCTGCCAGAGAGAACAGAATGGTCAGAGCCAGGGTG CGCCCGAGTGGCGGAGC 1371GCTCCGCCACTCGGGCG 1372 MelanomaTCTGACCACTCTGCTCTCTCTGGCAGGTCATGATGATGGGCAT 1373 Leu62ProGCGCCCGCGTGGCGGAGCTGCTGCTGCTCCACGGCGCGGA CTG-CCGGCCCAACTGCGCAGACCCTGCCACTCTCACCCGACCGGTACCGGTCGGGTGAGAGTGGCAGGGTCTGCGCAGTTGGGCTC 1374CGCGCCGTGGAGCAGCAGCAGCTCCGCCACGCGGGCGCTGCCCATCATCATGACCTGCCAGAGAGAGCAGAGTGGTCAGA GGCGGAGCTGCTGCTGC 1375GCAGCAGCAGCTCCGCC 1376 MelanomaTCTGGCAGGTCATGATGATGGGCAGCGCCCGCGTGGCGGAG 1377 Ala68ValCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCAGACCC GCG-GTGTGCCACTCTCACCCGACCGGTGCATGATGCTGCCCGGGATCCCGGGCAGCATCATGCACCGGTCGGGTGAGAGTGGCAGG 1378GTCTGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCTCCGCCACGCGGGCGCTGCCCATCATCATGACCTGCCAGA CCACGGCGCGGAGCCCA 1379TGGGCTCCGCGCCGTGG 1380 MelanomaCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTGC 1381 Asn71LysTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTC AACt-AAAACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGCAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGA 1382GAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATG GAGCCCAACTGCGCCGA 1383TCGGCGCAGTTGGGCTC 1384 MelanomaTCATGATGATGGGCAGCGCCCGAGTGGCGGAGCTGCTGCTG 1385 Asn71SerCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCT AAC-AGCCACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAG 1386AGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCTCCGCCACTCGGGCGCTGCCCATCATCATGA GGAGCGCAACTGCGCCG 1387CGGCGCAGTTGGGCTCC 1388 MelanomaAGCTGCTGCTGCTCCACGGCGCGGAGCCCAACTGCGCCGAC 1389 Pro81LeuCCCGCCACTCTCACCCGACCCGTGCACGACGCTGCCCGGGA CCC-CTCGGGCTTCCTGGACACGCTGGTGGTGCTGCACCGGGCCGGCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTC 1390CCGGGCAGCGTCGTGCACGGGTCGGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAGCAGCAGCT CACCCGACCCGTGCACG 1391CGTGCACGGGTCGGGTG 1392 MelanomaCTGCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCAC 1393 Asp84TyrTCTCACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCC cGAC-TACTGGACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGG 1394AAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAGCAG CCGTGCACGACGCTGCC 1395GGCAGCGTCGTGCACGG 1396 MelanomaCTCCACGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCT 1397 Ala85ThrCACCCGACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGG cGCT-ACTACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCC 1398AGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCCGTGGAG TGCACGACGCTGCCCGG 1399CCGGGCAGCGTCGTGCA 1400 MelanomaGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACCCGA 1401 Arg87ProCCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGGACACGCT CGG-CCGGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGCGCGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAG 1402CGTGTCCAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGC CGCTGCCCGGGAGGGCT 1403AGCCCTCCCGGGCAGCG 1404 MelanomaGGCGCGGAGCCCAACTGCGCCGACCCCGCCACTCTCACCCG 1405 Arg87TrpACCCGTGCACGACGCTGCCCGGGAGGGCTTCCTGGACACGC cCGG-TGGTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGCGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGC 1406GTGTCCAGGAAGCCCTCCCGGGCAGCGTCGTGCACGGGTCGGGTGAGAGTGGCGGGGTCGGCGCAGTTGGGCTCCGCGCC ACGCTGCCCGGGAGGGC 1407GCCCTCCCGGGCAGCGT 1408 MelanomaCTCTCACCCGACCGGTGCATGATGCTGCCCGGGAGGGCTTC 1409 Leu97ArgCTGGACACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCT CTG-CGGGGACGTGCGCGATGCCTGGGGTCGTCTGCCCGTGGACTTAAGTCCACGGGCAGACGACCCCAGGCATCGCGCACGTCCAG 1410CCGCGCCCCGGCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTCCCGGGCAGCATCATGCACCGGTCGGGTGAGAG GGTGGTGCTGCACCGGG 1411CCCGGTGCAGCACCACC 1412 MelanomaCCCGACCGGTGCATGATGCTGCCCGGGAGGGCTTCCTGGAC 1413 Arg99ProACGCTGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACG CGG-CCGTGCGCGATGCCTGGGGTCGTCTGCCCGTGGACTTGGCCGATCGGCCAAGTCCACGGGCAGACGACCCCAGGCATCGCGCAC 1414GTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTCCCGGGCAGCATCATGCACCGGTCGGG GCTGCACCGGGCCGGGG 1415CCCCGGCCCGGTGCAGC 1416 MelanomaCCGGTGCATGATGCTGCCCGGGAGGGCTTCCTGGACACGCT 1417 Gly101TrpGGTGGTGCTGCACCGGGCCGGGGCGCGGCTGGACGTGCGC cGGG-TGGGATGCCTGGGGTCGTCTGCCCGTGGACTTGGCCGAGGAGCGCTCCTCGGCCAAGTCCACGGGCAGACGACCCCAGGCATCG 1418CGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTCCCGGGCAGCATCATGCACCGG ACCGGGCCGGGGCGCGG 1419CCGCGCCCCGGCCCGGT 1420 MelanomaCGGGAGGGCTTCCTGGACACGCTGGTGGTGCTGCACCGGGC 1421 Arg107CysCGGGGCGCGGCTGGACGTGCGCGATGCCTGGGGTCGTCTGC gCGC-TGCCCGTGGACTTGGCCGAGGAGCGGGGCCACCGCGACGTTGCAACGTCGCGGTGGCCCCGCTCCTCGGCCAAGTCCACGGGC 1422AGACGACCCCAGGCATCGCGCACGTCCAGCCGCGCCCCGGCCCGGTGCAGCACCACCAGCGTGTCCAGGAAGCCCTCCCG TGGACGTGCGCGATGCC 1423GGCATCGCGCACGTCCA 1424 Melanoma CACCGGGCCGGGGCGCGGCTGGACGTGCGCGATGCCTGGG1425 Ala118Thr GCCGTCTGCCCGTGGACCTGGCTGAGGAGCTGGGCCATCGC gGCT-ACTGATGTCGCACGGTACCTGCGCGCGGCTGCGGGGGGCACCATGGTGCCCCCCGCAGCCGCGCGCAGGTACCGTGCGACATCG 1426CGATGGCCCAGCTCCTCAGCCAGGTCCACGGGCAGACGGCCCCAGGCATCGCGCACGTCCAGCCGCGCCCCGGCCCGGTG TGGACCTGGCTGAGGAG 1427CTCCTCAGCCAGGTCCA 1428 MelanomaTGCGCGATGCCTGGGGCCGTCTGCCCGTGGACCTGGCTGAG 1429 Val126AspGAGCTGGGCCATCGCGATGTCGCACGGTACCTGCGCGCGGC GTC-GACTGCGGGGGGCACCAGAGGCAGTAACCATGCCCGCATAGATCTATGCGGGCATGGTTACTGCCTCTGGTGCCCCCCGCAGCC 1430GCGCGCAGGTACCGTGCGACATCGCGATGGCCCAGCTCCTCAGCCAGGTCCACGGGCAGACGGCCCCAGGCATCGCGCA TCGCGATGTCGCACGGT 1431ACCGTGCGACATCGCGA 1432

EXAMPLE 11 Adenomatous Polyposis of the Colon—APC

[0131] Adenomatous polyposis of the colon is characterized byadenomatous polyps of the colon and rectum; in extreme cases the bowelis carpeted with a myriad of polyps. This is a viciously premalignantdisease with one or more polyps progressing through dysplasia tomalignancy in untreated gene carriers with a median age at diagnosis of40 years.

[0132] Mutations in the APC gene are an initiating event for bothfamilial and sporadic colorectal tumorigenesis and many alleles of theAPC gene have been identified. Carcinoma may arise at any age from latechildhood through the seventh decade with presenting features including,for example, weight loss and inanition, bowel obstruction, or bloodydiarrhea. Cases of new mutation still present in these ways but in areaswith well organized registers most other gene carriers are detected. Theattached table discloses the correcting oligonucleotide base sequencesfor the APC oligonucleotides of the invention. TABLE 18 APC Mutationsand Genome-Correcting Oligos Clinical Phenotype & SEQ ID MutationCorrecting Oligos NO: Adenomatous polyposisGGATCTGTATCAAGCCGTTCTGGAGAGTGCAGTCCTGTTCCT 1433 coli ATGGGTTCATTTCCAAGAA GAGGGTTTGTAAATGGAAGCAGA Arg121TermGAAAGTACTGGATATTTAGAAGAACTTGAGAAAGAGA AGA-TGATCTCTTTCTCAAGTTCTTCTAAATATCCAGTACTTTCTCTGCTT 1434 CCATTTACAAACCCTC TTCTTGGAAATGAAACCCATAGGAACAG GACTGCACTCTCCAGAACGGCTTGATACAGATCC TTCCAAGAA GAGGGTTT 1435 AAACCCTC T TCTTGGAA 1436 Adenomatous polyposisAAAAAAAAAATAGGTCATTGCTTCTTGCTGATCTTGACAAAGAA 1437 coli GAAAAGGAAAAAGACTG GTATTACGCTCAACTTCAGAATCTCA Trp157TermCTAAAAGAATAGATAGTCTTCCTTTAACTGAAAA TGG-TAGTTTTCAGTTAAAGGAAGACTATCTATTCTTTTAGTGAGATTCTG 1438 AAGTTGAGCGTAATAC CAGTCTTTTTCCTTTTCTTCTTTGTCAA GATCAGCAAGAAGCAATGACCTATTTTTTTTTT AAAAGACT GGTATTACG 1439 CGTAATAC C AGTCTTTT 1440 Adenomatous polyposisAAATAGGTCATTGCTTCTTGCTGATCTTGACAAAGAAGAAAAG 1441 coli GAAAAAGACTGGTATTAC GCTCAACTTCAGAATCTCACTAAAA Tyr159TermGAATAGATAGTCTTCCTTTAACTGAAAATGTAAGT TAC-TAGACTTACATTTTCAGTTAAAGGAAGACTATCTATTTCTTTTAGTGA 1442 GATTCTGAAGTTGAGC GTAATACCAGTCTTTTTCCTTTTCTTCT TTGTCAAGATCAGCAAGAAGCAATGACCTATTT TGGTATTA CGCTCAACT 1443 AGTTGAGC G TAATACCA 1444 Adenomatous polyposisTTGCTTCTTGCTGATCTTGACAAAGAAGAAAAGGAAAAAGACT 1445 coli GGTATTACGCTCAACTTC AGAATCTCACTAAAAGAATAGATAG Gin163TermTCTTCCTTTAACTGAAAATGTAAGTAACTGGCAGT CAG-TAGACTGCCAGTTACTTACATTTTCAGTTAAAGGAAGACTATCTATT 1446 CTTTTAGTGAGATTCT GAAGTTGAGCGTAATACCAGTCTTTTTC CTTTTCTTCTTTGTCAAGATCAGCAAGAAGCAA CTCAACTT CAGAATCTC 1447 GAGATTCT G AAGTTGAG 1448 Adenomatous polyposisCTTGACAAAGAAGAAAAGGAAAAAGACTGGTATTACGCTCAAC 1449 coli TTCAGAATCTCACTAAAA GAATAGATAGTCTTCCTTTAACTGAA Arg168TermAATGTAAGTAACTGGCAGTACAACTTATTTGAAA AGA-TGATTTCAAATAAGTTGTACTGCCAGTTACTTACATTTTCAGTTAAA 1450 GGAAGACTATCTATTC TTTTAGTGAGATTCTGAAGTTGAGCGT AATACCAGTCTTTTTCCTTTTCTTCTTTGTCAAG TCACTAAA AGAATAGAT 1451 ATCTATTC T TTTAGTGA 1452 Adenomatous polyposisAAGAAAAGGAAAAAGACTGGTATTACGCTCAACTTCAGAATCT 1453 coli CACTAAAAGAATAGATAG TCTTCCTTTAACTGAAAATGTAAGTA Ser711IleACTGGCAGTACAACTTATTTGAAACTTTAATAAC AGT-ATTGTTATTAAAGTTTCAAATAAGTTGTACTGCCAGTTACTTACATT 1454 TTCAGTTAAAGGAAGA CTATCTATTCTTTTAGTGAGATTCTGAA GTTGAGCGTAATACCAGTCTTTTTCCTTTTCTT AATAGATA GTCTTCCTT 1455 AAGGAAGA C TATCTATT 1456 Adenomatous polyposisGATTAACGTAAATACAAGATATTGATACTTTTTTATTATTTGTGG 1457 coli TTTTAGTTTTCCTTAC AAACAGATATGACCAGAAGGCAATTGG Gln181TermAATATGAAGCAAGGCAAATCAGAGTTGCGATGG CAA-TAACCATCGCAACTCTGATTTGCCTTGCTTCATATTCCAATTGCCT 1458 TCTGGTCATATCTGTTT GTAAGGAAAACTAAAACCACAAATAAT AAAAAAGTATCAATATCTTGTATTTACGTTAATC TTTCCTTA CAAACAGAT 1459 ATCTGTTT G TAAGGAAA 1460 Adenomatous polyposisCTTTTTTATTATTTGTGGTTTTAGTTTTCCTTACAAACAGATATG 1461 coli ACCAGAAGGCAATTGG AATATGMGCAAGGCAAATCAGAGTT Glu190TermGCGATGGAAGAACAACTAGGTACCTGCCAGGATA GAA-TAATATCCTGGCAGGTACCTAGTTGTTCTTCCATCGCAACTCTGAT 1462 TTGCCTTGCTTCATATTT CCAATTGCCTTCTGGTCATATCTGTTT GTAAGGAAAACTAAAACCACAAATAATAAAAAAG GGCAATTG GAATATGAA 1463 TTCATATT C CAATTGCC 1464 Adenomatous polyposisCAATTGGAATATGAAGCAAGGCAAATCAGAGTTGCGATGGAA 1465 coli GAACAACTAGGTACCTGCC AGGATATGGAAAAACGAGCACAG Gln208TermGTAAGTTACTTGTTTCTAAGTGATAAAACAGCGAAGA CAG-TAGTCTTCGCTGTTTTATCACTTAGAAACAAGTAACTTACCTGTGCT 1466 CGTTTTTCCATATCCT GGCAGGTACCTAGTTGTTCTTCCATCG CAACTCTGATTTGCCTTGCTTCATATTCCAATTG GTACCTGC CAGGATATG 1467 CATATCCT G GCAGGTAC 1468 Adenomatous polyposisGCAAGGCAAATCAGAGTTGCGATGGAAGAACAACTAGGTACC 1469 coli TGCCAGGATATGGAAAAAC GAGCACAGGTAAGTTACTTGTTTC Arg213TermTAAGTGATAAAACAGCGAAGAGCTATTAGGAATAAA CGA-TGATTTATTCCTAATAGCTCTTCGCTGTTTTATCACTTTAGAAACAAG 1470 TAACTTACCTGTGCTC GTTTTTCCATATCCTGGCAGGTACCTA GTTGTTCTTCCATCGCAACTCTGATTTGCCTTGC TGGAAAAA CGAGCACAG 1471 CTGTGCTC G TTTTTCCA 1472 Adenomatous polyposisGTTTTATTTTAGCGAAGAATAGCCAGAATTCAGCAAATCGAAA 1473 coli AGGACATACTTCGTATAC GACAGCTTTTACAGTCCCAAGCAAC Arg232TermAGAAGCAGAGGTTAGTAAATTGCCTTTCTTGTTTG CGA-TGACAAACAAGAAAGGCAATTTACTAACCTCTGCTTCTGTTGCTTG 1474 GGACTGTAAAAGCTGTC GTATACGAAGTATGTCCTTTTCGATT TGCTGAATTCTGGCTATTCTTCGCTAAAATAAAAC TTCGTATA CGACAGCTT 1475 AAGCTGTC G TATACGAA 1476 Adenomatous polyposisTTATTTTAGCGAAGAATAGCCAGAATTCAGCAAATCGAAAAGG 1477 coli ACATACTTCGTATACGAC AGCTTTTACAGTCCCAAGCAACAGA Gln233TermAGCAGAGGTTAGTAAATTGCCTTTCTTGTTTGTGG CAG-TAGCCACAAACAAGAAAGGCAATTTACTAACCTCTGCTTCTGTTGC 1478 TTGGGACTGTAAAAGCT GTCGTATACGAAGTATGTCCTTTTCG ATTTGCTGAATTCTGGCTATTCTTCGCTAAAATAA GTATACGA CAGCTTTTA 1479 TAAAAGCT G TCGTATAC 1480 Adenomatous polyposisAGAAAGCCTACACCATTTTTGCATGTACTGATGTTAACTCCAT 1481 coli CTTAACAGAGGTCATCTC AGAACAAGCATGAAACCGGCTCAC Gln247TermATGATGCTGAGCGGCAGAATGAAGGTCAAGGAGTGG CAG-TAGCCACTCCTTGACCTTCATTCTGCCGCTCAGCATCATGTGAGC 1482 CGGTTTCATGCTTGTTCT GAGATGACCTCTGTTAAGATGGAGT TAACATCAGTACATGCAAAAATGGTGTAGGCTTTCT GGTCATCT CAGAACAAG 1483 CTTGTTCT G AGATGACC 1484 Adenomatous polyposisCAGAACAAGCATGAAACCGGCTCACATGATGCTGAGCGGCAG 1485 coli AATGAAGGTCAAGGAGTGG GAGAAATCAACATGGCAACTTCT Gly267TermGGTAATGGTCAGGTAAATAAATTATTTTATCATATTT GGA-TGAAAATATGATAAAATAATTTATTTACCTGACCATTACCAGAAGTT 1486 GCCATGTTGATTTCTC CCACTCCTTGACCTTCATTCTGCCGCT CAGCATCATGTGAGCCGGTTTCATGCTTGTTCTG AAGGAGTG GGAGAAATC 1487 GATTTCTC C CACTCCTT 1488 Adenomatous polyposisCTTCAAATAACAAAGCATTATGGTTTATGTTGATTTTATTTTTCA 1489 coli GTGCCAGCTCCTGTTG AACATCAGATCTGTCCTGCTGTGTGT Glu443TermGTTCTAATGAAACTTTCATTTGATGAAGAGCATA GAA-TAATATGCTCTTCATCAAATGAAAGTTTCATTAGAACACACACAGCA 1490 GGACAGATCTGATGTT CAACAGGAGCTGGCACTGAAAAATAA AATCAACATAAACCATAATGCTTTGTTATTTGAAG CTCCTGTT GAACATCAG 1491 CTGATGTT C AACAGGAG 1492 Adenomatous polyposisCAGTGCCAGCTCCTGTTGAACATCAGATCTGTCCTGCTGTGT 1493 coli GTGTTCTAATGAAACTTTC ATTTGATGAAGAGCATAGACATGC SER457TERAATGAATGAACTAGGTAAGACAAAAATGTTTTTTAA TCA-TAATTAAAAAACATTTTTGTCTTACCTAGTTCATTGCATTGCATGTCTA 1494 TGCTCTTCATCAAAT GAAAGTTTCATTAGAACACACACAGCAG GACAGATCTGATGTTCAACAGGAGCTGGCACTG GAAACTTT CATTTGATG 1495 CATCAAAT G AAAGTTTC 1496 Adenomatous polyposisAGTTGTTTTATTTTAGATGATTGTCTTTTTCCTCTTGCCCTTTTT 1497 coli AAATTAGGGGGACTAC AGGCCATTGCAGAATTATTGCAAGTG Gln473TermGACTGTGAAATGTACGGGCTTACTAATGACCACT CAG-TAGAGTGGTCATTAGTAAGCCCGTACATTTCACAGTCCACTTGCAA 1498 TAATTCTGCAATGGCCT GTAGTCCCCCTAATTTAAAAAGGGCA AGAGGAAAAAGACAATCATCTAAAATAAAACAACT GGGGACTA CAGGCCATT 1499 AATGGCCT G TAGTCCCC 1500 Adenomatous polyposisTTTTAAATTAGGGGGACTACAGGCCATTGCAGAATTATTGCAA 1501 coli GTGGACTGTGAAATGTAC GGGCTTACTAATGACCACTACAGTA Tyr486TermTTACACTAAGACGATATGCTGGAATGGCTTTGACA TAC-TAGTGTCAAAGCCATTCCAGCATATCGTCTTAGTGTAATACTGTAG 1502 TGGTCATTAGTAAGCCC GTACATTTCACAGTCCACTTGCAATA ATTCTGCAATGGCCTGTAGTCCCCCTAATTTAAAA GAAATGTA CGGGCTTAC 1503 GTAAGCCC G TACATTTC 1504 Adenomatous polyposisTTGCAAGTGGACTGTGAAATGTATGGGCTTACTAATGACCACT 1505 coli ACAGTATTACACTAAGAC GATATGCTGGAATGGCTTTGACAAA Arg499TermCTTGACTTTTGGAGATGTAGCCAACAAGGTATGTT CGA-TGAAACATACCTTGTTGGCTACATCTCCAAAAGTCAAGTTTGTCAA 1506 AGCCATTCCAGCATATC GTCTTAGTGTAATACTGTAGTGGTCA TTAGTAAGCCCATACATTTCACAGTCCACTTGCAA CACTAAGA CGATATGCT 1507 AGCATATC G TCTTAGTG 1508 Adenomatous polyposisAGTGGACTGTGAAATGTATGGGCTTACTAATGACCACTACAGT 1509 coli ATTACACTAAGACGATAT GCTGGAATGGCTTTGACAAACTTGA Tyr500TermCTTTTGGAGATGTAGCCAACAAGGTATGTTTTTAT TAT-TAGATAAAAACATACCTTGTTGGCTACATCTCCAAAAGTCAAGTTTG 1510 TCAAAGCCATTCCAGC ATATCGTCTTAGTGTAATACTGTAGTG GTCATTAGTAAGCCCATACATTTCACAGTCCACT AGACGATA TGCTGGAAT 1511 ATTCCAGC A TATCGTCT 1512 Adenomatous polyposisGACAAATTCCAACTCTAATTAGATGACCCATATTCTGTTTCTTA 1513 coli CTAGGAATCAACCCTCA AAAGCGTATTGAGTGCCTTATGGAAT Lys586TermTTGTCAGCACATTGCACTGAGAATAAAGCTGATA AAA-TAATATCAGCTTTATTCTCAGTGCAATGTGCTGACAAATTCCATAA 1514 GGCACTCAATACGCTTT TGAGGGTTGATTCCTAGTAAGAAACA GAATATGGGTCATCTAATTAGAGTTGGAATTTGTC CAACCCTC AAAAGCGTA 1515 TACGCTTT T GAGGGTTG 1516 Adenomatous polyposisTAGATGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAA 1517 coli AGCGTATTGAGTGCCTT ATGGAATTTGTCAGCACATTGCACTG Leu592TermAGAATAAAGCTGATATATGTGCTGTAGATGGTGC TTA-TGAGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTGCAAT 1518 GTGCTGACAAATTCCAT AAGGCACTCAATACGCTTTTGAGGGT TGATTCCTAGTAAGAAACAGAATATGGGTCATCTA GAGTGCCT TATGGAATT 1519 AATTCCAT A AGGCACTC 1520 Adenomatous polyposisATGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAAAG 1521 coli CGTATTGAGTGCCTTATG GAATTTGTCAGCACATTGCACTGAG Trp593TermAATAAAGCTGATATATGTGCTGTAGATGGTGCACT TGG-TAGAGTGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTGC 1522 AATGTGCTGACAAATTC CATAAGGCACTCAATACGCTTTTGAG GGTTGATTCCTAGTAAGAAACAGAATATGGGTCAT TGCCTTAT GGAATTTGT 1523 ACAAATTC C ATAAGGCA 1524 Adenomatous polyposisTGACCCATATTCTGTTTCTTACTAGGAATCAACCCTCAAAAGC 1525 coli GTATTGAGTGCCTTATGG AATTTGTCAGCACATTGCACTGAGA Trp593TermATAAAGCTGATATATGTGCTGTAGATGGTGCACTT TGG-TGAAAGTGCACCATCTACAGCACATATATCAGCTTTATTCTCAGTG 1526 CAATGTGCTGACAAATT CCATAAGGCACTCAATACGCTTTTGA GGGTTGATTCCTAGTAAGAAACAGAATATGGGTCA GCCTTATG GAATTTGTC 1527 GACAAATT C CATAAGGC 1528 Adenomatous polyposisTAAAGCTGATATATGTGCTGTAGATGGTGCACTTGCATTTTTG 1529 coli GTTGGCACTCTTACTTAC CGGAGCCAGACAAACACTTTAGCC Tyr622TermATTATTGAAAGTGGAGGTGGGATATTACGGAATGTG TAG-TAACACATTCCGTAATATCCCACCTCCACTTTCAATAATGGCTAAA 1530 GTGTTTGTCTGGCTCCG GTAAGTAAGAGTGCCAACCAAAAAT GCAAGTGCACCATCTACAGCACATATATCAGCTTTA CTTACTTA CCGGAGCCA 1531 TGGCTCCG G TAAGTAAG 1532 Adenomatous polyposisGATATATGTGCTGTAGATGGTGCACTTGCATTTTTGGTTGGCA 1533 coli CTCTTACTTACCGGAGCC AGACAAACACTTTAGCCATTATTGA Gln625TermAAGTGGAGGTGGGATATTACGGAATGTGTCCAGCT GAG-TAGAGCTGGACACATTCCGTAATATCCCACCTGCACTTTCAATAAT 1534 GGCTAAAGTGTTTGTCT GGCTCCGGTAAGTAAGAGTGCCAAC CAAAAATGCAAGTGCACCATCTACAGCACATATATC ACCGGAGC CAGACAAAC 1535 GTTTGTCT G GCTCCGGT 1536 Adenomatous polyposisTAGATGGTGCACTTGCATTTTTGGTTGGCACTCTTACTTACCG 1537 coli GAGCCAGACAAACACTTT AGCCATTATTGAAAGTGGAGGTGG Leu629TermGATATTACGGAATGTGTCCAGCTTGATAGCTACAAA TTA-TAATTTGTAGCTATCAAGCTGGACACATTCCGTAATATCCCACCTC 1538 CACTTTCAATAATGGCT AAAGTGTTTGTCTGGCTCCGGTAAGT AAGAGTGCCAACCAAAAATGCAAGTGCACCATCTA AAACACTT TAGCCATTA 1539 TAATGGCT A AAGTGTTT 1540 Adenomatous polyposisGCCATTATTGAAAGTGGAGGTGGGATATTTACGGAATGTGTCC 1541 coli AGCTTGATAGCTACAAATG AGGACCACAGGTATATATAGAGTT Glu650TermTTATATTACTTTTAAAGTACAGAATTCATACTCTCA GAG-TAGTGAGAGTATGAATTCTGTACTTTAAAAGTAATATAAAACTCTAT 1542 ATATACCTGTGGTCCT CATTTGTAGCTATCAAGCTGGACACAT TCCGTAATATCCCACCTCCACTTTCAATAATGGC CTACAAAT GAGGACCAC 1543 GTGGTCCT C ATTTGTAG 1544 Adenomatous polyposisTGCATGTGGAACTTTGTGGAATCTCTCAGCAAGAAATCCTAAA 1545 coli GACCAGGAAGCATTATGG GACATGGGGGCAGTTAGCATGCTC Trp699TermAAGAACCTCATTCATTCAAAGCACAAAATGATTGCT TGG-TGAAGCAATCATTTTGTGCTTTGAATGAATGAGGTTCTTGAGCATG 1546 CTAACTGCCCCCATGTC CCATAATGCTTCCTGGTCTTTAGGAT TTCTTGCTGAGAGATTCCACAAAGTTCCACATGCA GCATTATG GGACATGGG 1547 CCCATGTC C CATAATGC 1548 Adenomatous polyposisAAGACCAGGAAGCATTATGGGACATGGGGGCAGTTAGCATGC 1549 coli TCAAGAACCTCATTCATTC AAAGCACAAAATGATTGCTATGGG Ser713TermAAGTGCTGCAGCTTTAAGGAATCTCATGGCAAATAG TCA-TGACTATTTGCCATGAGATTCCTTAAAGCTGCAGCACTTCCCATAG 1550 CAATCATTTTGTGCTTT GAATGAATGAGGTTCTTGAGCATGCT AACTGCCCCCATGTCCCATAATGCTTCCTGGTCTT CATTCATT CAAAGCACA 1551 TGTGCTTT G AATGAATG 1552 Adenomatous polyposisGGGGCAGTTAGCATGCTCAAGAACCTCATTCATTCAAAGCAC 1553 coli AAAATGATTGCTATGGGAA GTGCTGCAGCTTTAAGGAATCTCA Ser722GlyTGGCAAATAGGCCTGCGAAGTACAAGGATGCCAATA AGT-GGTTATTGGCATCCTTGTACTTCGCAGGCCTATTTGCCATGAGATT 1554 CCTTAAAGCTGCAGCAC TTCCCATAGCAATCATTTTGTGCTTT GAATGAATGAGGTTCTTGAGCATGCTAACTGCCCC CTATGGGA AGTGCTGCA 1555 TGCAGCAC T TCCCATAG 1556 Adenomatous polyposisTCTCCTGGCTCAGCTTGCCATCTCTTCATGTTAGGAAACAAAA 1557 coli AGCCCTAGAAGCAGAATT AGATGCTCAGCACTTATCAGAAACT Leu764TermTTTGACAATATAGACAATTTAAGTCCCAAGGCATC TTA-TAAGATGCCTTGGGACTTAAATTGTCTATATTGTCAAAAGTTTCTGA 1558 TAAGTGCTGAGCATCT AATTCTGCTTCTAGGGCTTTTTGTTTC CTAACATGAAGAGATGGCAAGCTGAGCCAGGAGA AGCAGAAT TAGATGCTC 1559 GAGCATCT A ATTCTGCT 1560 Adenomatous polyposisTTAGATGCTCAGCACTTATCAGAAACTTTTGACAATATAGACAA 1561 coli TTTAAGTCCCAAGGCAT CTCATCGTAGTAAGCAGAGACACAG Ser784ThrCAAGTCTCTATGGTGATTATGTTTTTGACACCATC TCT-ACTGATGGTGTCAAAAACATAATCACCATAGAGACTTGCTGTGTCT 1562 CTGCTTACTACGATGAG ATGCCTTGGGACTTAAATTGTCTATA TTGTCAAAAGTTTCTGATAAGTGCTGAGCATCTAA CCAAGGCA TCTCATCGT 1563 ACGATGAG A TGCCTTGG 1564 Adenomatous polyposisCTCATCGTAGTAAGCAGAGACACAGCAAGTCTCTATGGTGATT 1565 coli ATGTTTTTGACACCAATC GACATGATGATAATAGGTCAGACAT Arg805TermTTTAATACTGGCACATGACTGTCCTTTCACCATAT CGA-TGAATATGGTGAAAGGACAGTCATGTGCCAGTATTAAAATGTCTGA 1566 CCTATTATCATCATGTC GATTGGTGTCAAAAACATAATCACCAT AGAGACTTGCTGTGTCTCTGCTTACTACGATGAG ACACCAAT CGACATGAT 1567 ATCATGTC G ATTGGTGT 1568 Adenomatous polyposisGGTCTAGGCAACTACCATCCAGCAACAGAAAATCCAGGAACT 1569 coli TCTTCAAAGCGAGGTTTGC AGATCTCCACCACTGCAGCCCAG Gln879TermATTGCCAAAGTCATGGAAGAAGTGTCAGCCATTCATA CAG-TAGTATGAATGGCTGACACTTCTTCCATGACTTTGGCAATCTGGGC 1570 TGCAGTGGTGGAGATCT GCAAACCTCGCTTTGAAGAAGTTCC TGGATTTTCTGTTGCTGGATGGTAGTTGCCTAGACC GAGGTTTG CAGATCTCC 1571 GGAGATCT G CAAACCTC 1572 Adenomatous polyposisTACATTGTGTGACAGATGAGAGAAATGCACTTAGAAGAAGCTC 1573 coli TGCTGCCCATACACATTC AAACACTTACAATTTCACTAAGTCG Ser932TermGAAAATTCAAATAGGACATGTTCTATGCCTTATGC TCA-TAAGCATAAGGCATAGAACATGTCCTATTTGAATTTTCCGACTTAG 1574 TGAAATTGTAAGTGTTT GAATGTGTATGGGCAGCAGAGCTTCT TCTAAGTGCATTTCTCTCATCTGTCACACAATGTA TACACATT CAAACACTT 1575 AAGTGTTT G AATGTGTA 1576 Adenomatous polyposisTACATTGTGTGACAGATGAGAGAAATGCACTTAGAAGAAGCTC 1577 coli TGCTGCCCATACACATTC AAACACTTACAATTTCACTAAGTCG I Ser932TermGAAAATTCAAATAGGACATGTTCTATGCCTTATGC TCA-TGAGCATAAGGCATAGAACATGTCCTATTTGAATTTTCCGACTTAG 1578 TGAAATTGTAAGTGTTT GAATGTGTATGGGCAGCAGAGCTTCT TCTAAGTGCATTTCTCTCATCTGTCACACAATGTA TACACATT CAAACACTT 1579 AAGTGTTT G AATGTGTA 1580 Adenomatous polyposisGACAGATGAGAGAAATGCACTTAGAAGAAGCTCTGCTGCCCA 1581 coli TACACATTCAAACACTTAC AATTTCACTAAGTCGGAAAATTCAA Tyr935TermATAGGACATGTTCTATGCCTTATGCCAAATTAGAA TAC-TAGTTCTAATTTGGCATAAGGCATAGAACATGTCCTATTTGAATTTT 1582 CCGACTTAGTGAAATT GTAAGTGTTTGAATGTGTATGGGCAGC AGAGCTTCTTCTAAGTGCATTTCTCTCATCTGTC AACACTTA CAATTTCAC 1583 GTGAAATT G TAAGTGTT 1584 Adenomatous polyposisGACAGATGAGAGAAATGCACTTAGAAGAAGCTCTGCTGCCCA 1585 coli TACACATTCAAACACTTAC AATTTCACTAAGTCGGAAAATTCAA Tyr935TermATAGGACATGTTCTATGCCTTATGCCAAATTAGAA TAC-TAATTCTAATTTGGCATAAGGCATAGAACATGTCCTATTTGAATTTT 1586 CCGACTTAGTGAAATT GTAAGTGTTTGAATGTGTATGGGCAGC AGAGCTTCTTCTAAGTGCATTTCTCTCATCTGTC AACACTTA CAATTTCAC 1587 GTGAAATT G TAAGTGTT 1588 Adenomatous polyposisACCCTCGATTGAATCCTATTCTGAAGATGATGAAAGTAAGTTTT 1589 coli GCAGTTATGGTCAATAC CCAGCCGACCTAGCCCATAAAATACA Tyr1000TermTAGTGCAAATCATATGGATGATAATGATGGAGAA TAC-TAATTCTCCATCATTATCATCCATATGATTTGCACTATGTATTTTAT 1590 GGGCTAGGTCGGCTGG GTATTGACCATAACTGCAAAACTTAC TTTCATCATCTTCAGAATAGGATTCAATCGAGGGT GGTCAATA CCCAGCCGA 1591 TCGGCTGG G TATTGACC 1592 Adenomatous polyposisTACCCAGCCGACCTAGCCCATAAAATACATAGTGCAAATCATA 1593 coli TGGATGATAATGATGGAG AACTAGATACACCAATAAATTATAG Glu1020TermTCTTAAATATTCAGATGAGCAGTTGAACTCTGGAA GAA-TAATTCCAGAGTTCAACTGCTCATCTGAATATTTAAGACTATAATTT 1594 ATTGGTGTATCTAGTT CTCCATCATTATCATCCATATGATTTGC ACTATGTATTTTATGGGCTAGGTCGGCTGGGTA ATGATGGA GAACTAGAT 1595 ATCTAGTT C TCCATCAT 1596 Adenomatous polyposisATGAAACCCTCGATTGAATCCTATTCTGAAGATGATGAAAGTA 1597 coli AGTTTTGCAGTTATGGTC AATACCCAGCCGACCTAGCCCATAA Ser1032TermAATACATAGTGCAAATCATATGGATGATAATGATG TCA-TAACATCATTATCATCCATATGATTTGCACTATGTATTTTATGGGCT 1598 AGGTCGGCTGGGTATT GACCATAACTGCAAAACTTACTTTCAT CATCTTCAGAATAGGATTCAATCGAGGGTTTCAT GTTATGGT CAATACCCA 1599 TGGGTATT G ACCATAAC 1600 Adenomatous polyposisTGAAGATGATGAAAGTAAGTTTTGCAGTTATGGTCAATACCCA 1601 coli GCCGACCTAGCCCATAAA ATACATAGTGCAAATCATATGGATG Gln1041TermATAATGATGGAGAACTAGATACACCAATAAATTAT CAA-TAAATAATTTATTGGTGTATCTAGTTCTCCATCATTATCATCCATAT 1602 GATTTGCACTATGTAT TTTATGGGCTAGGTCGGCTGGGTATTG ACCATAACTGCAAAACTTACTTTCATCATCTTCA GCCCATAA AATACATAG 1603 CTATGTAT T TTATGGGC 1604 Adenomatous polyposisATAAATTATAGTCTTAAATATTCAGATGAGCAGTTGAACTCTGG 1605 coli AAGGCAAAGTCCTTCAC AGAATGAAAGATGGGCAAGACCCAA Gln1045TermACACATAATAGAAGATGAAATAAAACAAAGTGAGC CAG-TAGGCTCACTTTGTTTTATTTCATCTTCTATTATGTGTTTGGGTCTT 1606 GCCCATCTTTCATTCT GTGAAGGACTTTGCCTTCCAGAGTTCA ACTGCTCATCTGAATATTTAAGACTATAATTTAT GTCCTTCA CAGAATGAA 1607 TTCATTCT G TGAAGGAC 1608 Adenomatous polyposisGAAAGATGGGCAAGACCCAAACACATAATAGAAGATGAAATAA 1609 coli AACAAAGTGAGCAAAGAC AATCAAGGAATCAAAGTACAACTTA Gln1067TermTCCTGTTTATACTGAGAGCACTGATGATAAACACC CAA-TAAGGTGTTTATCATCAGTGCTCTCAGTATAAACAGGATAAGTTGT 1610 ACTTTGATTCCTTGATT GTCTTTGCTCACTTTGTTTTATTTCATC TTCTATTATGTGTTTGGGTCTTGCCCATCTTTC AGCAAAGA CAATCAAGG 1611 CCTTGATT G TCTTTGCT 1612 Adenomatous polyposisAATAGAAGATGAAATAAAACAAAGTGAGCAAAGACAATCAAGG 1613 coli AATCAAAGTACAACTTAT CCTGTTTATACTGAGAGCACTGATG Tyr1075TermATAAACACCTCAAGTTCCAACCACATTTTGGACAG TAT-TAGCTGTCCAAAATGTGGTTGGAACTTGAGGTGTTTATCATCAGTG 1614 CTCTCAGTATAAACAGG ATAAGTTGTACTTTGATTCCTTGATTG TCTTTGCTCACTTTGTTTTATTTCATCTTCTATT ACAACTTA TCCTGTTTA 1615 TAAACAGG A TAAGTTGT 1616 Adenomatous polyposisTGATGATAAACACCTCAAGTTCCAACCACATTTTGGACAGCAG 1617 coli GAATGTGTTTCTCCATAC AGGTCACGGGGAGCCAATGGTTCA Tyr1102TermGAAACAAATCGAGTGGGTTCTAATCATGGAATTAAT TAC-TAGATTAATTCCATGATTAGAACCCACTCGATTTGTTTCTGAACCAT 1618 TGGCTCCCCGTGACCT GTATGGAGAAACACATTCCTGCTGTC CAAAATGTGGTTGGAACTTGAGGTGTTTATCATCA TCTCCATA CAGGTCACG 1619 CGTGACCT G TATGGAGA 1620 Adenomatous polyposisAACCACATTTTGGACAGCAGGAATGTGTTTCTCCATACAGGTC 1621 coli ACGGGGAGCCAATGGTTC AGAAACAAATCGAGTGGGTTCTAA Ser1110TermTCATGGAATTAATCAAAATGTAAGCCAGTCTTTGTG TCA-TGACACAAAGACTGGCTTACATTTTGATTAATTCCATGATTAGAACC 1622 CACTCGATTTGTTTCT GAACCATTGGCTCCCCGTGACCTGTAT GGAGAAACACATTCCTGCTGTCCAAAATGTGGTT CAATGGTT CAGAAACAA 1623 TTGTTTCT G AACCATTG 1624 Adenomatous polyposisGGACAGCAGGAATGTGTTTCTCCATACAGGTCACGGGGAGCC 1625 coli AATGGTTCAGAAACAAATC GAGTGGGTTCTAATCATGGAATTA Arg1114TermATCAAAATGTAAGCCAGTCTTTGTGTCAAGAAGATG GGA-TGACATCTTCTTGACACAAAGACTGGCTTACATTTTGATTAATTCCA 1626 TGATTAGAACCCACTC GATTTGTTTCTGAACCATTGGCTCCCC GTGACCTGTATGGAGAAACACTTCCTGCTGTCC AAACAAAT CGAGTGGGT 1627 ACCCACTC G ATTTGTTT 1628 Adenomatous polyposisGGGTTCTAATCATGGAATTAATCAAAATGTAAGCCAGTCTTTG 1629 coli TGTCAAGAAGATGACTAT GAAGATGATAAGCCTACCAATTATA Tyr1135TermGTGAACGTTACTCTGAAGAAGAACAGCATGAAGAA TAT-TAGTTCTTCATGCTGTTCTTCTTCAGAGTAACGTTCACTATAATTGG 1630 TAGGCTTATCATCTTC ATAGTCATCTTCTTGACACAAAGACTG GCTTACATTTTGATTAATTCCATGATTAGAACCC GATGACTA TGAAGATGA 1631 TCATCTTC A TAGTCATC 1632 Adenomatous polyposisGAAGATGACTATGAAGATGATAAGCCTACCAATTATAGTGAAC 1633 coli GTTACTCTGAAGAAGAAC AGCATGAAGAAGAAGAGAGACCAA Gln1152TermCAAATTATAGCATAAAATATAATGAAGAGAAACGTC GAG-TAGGACGTTTCTCTTCATTATATTTTATGCTATAATTTGTTGGTCTCT 1634 CTTCTTCTTCATGCT GTTCTTCTTCAGAGTAACGTTCACTATAA TTGGTAGGCTTATCATCTTCATAGTCATCTTC AAGAAGAA CAGCATGAA 1635 TTCATGCT G TTCTTCTT 1636 Adenomatous polyposisGAAGAAGAGAGACCAACAAATTATAGCATAAAATATAATGAAG 1637 coli AGAAACGTCATGTGGATC AGCCTATTGATTATAGTTTAAAATAT Gln1175TermGCCACAGATATTCCTTCATCACAGAAACAGTCAT CAG-TAGATGACTGTTTCTGTGATGAAGGAATATCTGTGGCATATTTTAAA 1638 CTATAATCAATAGGCT GATCCACATGACGTTTCTCTTCATTATA TTTTATGCTATAATTTGTTGGTCTCTCTTCTTC ATGTGGAT CAGCCTATT 1639 AATAGGCT G ATCCACAT 1640 Adenomatous polyposisAAGAGAGACCAACAAATTATAGCATAAAATATAATGAAGAGAA 1641 coli ACGTCATGTGGATCAGCC TATTGATTATAGTTTAAAATATGCCA Pro1176LeuCAGATATTCCTTCATCACAGAAACAGTCATTTTC CCT-CTTGAAAATGACTGTTTCTGTGATGAAGGAATATCTGTGGCATATT 1642 TTAAACTATAATCAATA GGCTGATCCACATGACGTTTCTCTTCA TTATATTTTATGCTATAATTTGTTGGTCTCTCTT GGATCAGC CTATTGATT 1643 AATCAATA G GCTGATCC 1644 Adenomatous polyposisATAAAATATAATGAAGAGAAACGTCATGTGGATCAGCCTATTG 1645 coli ATTATAGTTTAAAATATG CCACAGATATTCCTTCATCACAGAAA Ala1184ProCAGTCATTTTCATTCTCAAAGAGTTCATCTGGAC GCC-CCCGTCCAGATGAACTCTTTGAGAATGAAAATGACTGTTTCTGTGA 1646 TGAAGGAATATCTGTGG CATATTTTAAACTATAATCAATAGGCT GATCCACATGACGTTTCTCTTCATTATATTTTAT TAAAATAT GCCACAGAT 1647 ATCTGTGG C ATATTTTA 1648 Adenomatous polyposisATCAGCCTATTGATTATAGTTTAAAATATGCCACAGATATTCCT 1649 coli TCATCACAGAAACAGTC ATTTTCATTCTCAAAGAGTTCATCTG Ser1194TermGACAAAGCAGTAAAACCGAACATATGTCTTCAAG TCA-TGACTTGAAGACATATGTTCGGTTTTACTGCTTTGTCCAGATGAAC 1650 TCTTTGAGAATGAAAAT GACTGTTTCTGTGATGAAGGAATATCT GTGGCATATTTTAAACTATAATCAATAGGCTGAT GAAACAGT CATTTTCAT 1651 ATGAAAAT G ACTGTTTC 1652 Adenomatous polyposisATTATAGTTTAAAATATGCCACAGATATTCCTTCATCACAGAAA 1653 coli CAGTCATTTTCATTCTC AAAGAGTTCATCTGGACAAAGCAGTA Ser1198TermAAACCGAACATATGTCTTCAAGCAGTGAGAATAC TCA-TGAGTATTCTCACTGCTTGAAGACATATGTTCGGTTTTACTGCTTTG 1654 TCCAGATGAACTCTTT GAGAATGAAAATGACTGTTTCTGTGAT GAAGGAATATCTGTGGCATATTTTAAACTATAAT TTCATTCT CAAGAGTT 1655 AACTCTTT G AGAATGAA 1656 Adenomatous polyposisACCGAACATATGTCTTCAAGCAGTGAGAATACGTCCACACCTT 1657 coli CATCTAATGCCAAGAGGC AGAATCAGCTCCATCCAGTTCTGC Gln1228TermACAGAGTAGAAGTGGTCAGCCTCAAAGGCTGCCACT CAG-TAGAGTGGCAGCCTTTGAGGCTGACCACTTCTACTCTGTGCAGAA 1658 CTGGATGGAGCTGATTCT GCCTCTTGGCATTAGATGAAGGTG TGGACGTATTCTCACTGCTTGAAGACATATGTTCGGT CCAAGAGG CAGAATCAG 1659 CTGATTCT G CCTCTTGG 1660 Adenomatous polyposisCATATGTCTTCAAGCAGTGAGAATACGTCCACACCTTCATCTA 1661 coli ATGCCAAGAGGCAGAATC AGCTCCATCCAGTTCTGCACAGAG Gln1230TermTAGAAGTGGTCAGCCTCAAAGGCTGCCACTTGCAAG CAG-TAGCTTGCAAGTGGCAGCCTTTGAGGCTGACCACTTCTACTCTGT 1662 GCAGAACTGGATGGAGCT GATTCTGCCTCTTGGCATTAGATG AAGGTGTGGACGTATTCTCACTGCTTGAAGACATATG GGCAGAAT CAGCTCCAT 1663 ATGGAGCT G ATTCTGCC 1664 Adenomatous polyposisTCAGCTCCATCCAAGTTCTGCACAGAGTAGAAGTGGTCAGCC 1665 coli TCAAAAGGCTGCCACTTGC AAAGTTTCTTCTATTAACCAAGAA Cys1249TermACAATACAGACTTATTGTGTAGAAGATACTCCAATA TGC-TGATATTGGAGTATCTTCTACACAATAAGTCTGTATTGTTTCTTGGT 1666 TAATAGAAGAAACTTT GCAAGTGGCAGCCTTTTGAGGCTGACC ACTTCTACTCTGTGCAGAACTTGGATGGAGCTGA GCCACTTG CAAAGTTTC 1667 GAAACTTT G CAAGTGGC 1668 Adenomatous polyposisAGTTTCTTCTATTAACCAAGAAACAATACAGACTTATTGTGTAG 1669 coli AAGATACTCCAATATGT TTTTCAAGATGTAGTTCATTATCATCT Cys1270TermTTGTCATCAGCTGAAGATGAAATAGGATGTAAT TGT-TGAATTACATCCTATTTCATCTTCAGCTGATGACAAAGATGATAATG 1670 AACTACATCTTGAAAA ACATATTGGAGTATCTTCTACACAATAA GTCTGTATTGTTTCTTGGTTAATAGAAGAAACT CCAATATG TTTTTCAAG 1671 CTTGAAAA A CATATTGG 1672 Adenomatous polyposisAAGAAACAATACAGACTTATTGTGTAGAAGATACTCCAATATGT 1673 coli TTTTCAAGATGTAGTTC ATTATCATCTTTGTCATCAGCTGAAGA Ser1276TermTGAAATAGGATGTAATCAGACGACACAGGAAGC TCA-TGAGCTTCCTGTGTCGTCTGATTACATCCTATTTCATCTTCAGCTG 1674 ATGACAAAGATGATAAT GAACTACATCTTGAAAAACATATTGGA GTATCTTCTACACAATAAGTCTGTATTGTTTCTT ATGTAGTT CATTATCAT 1675 ATGATAAT G AACTACAT 1676 Adenomatous polyposisGATACTCCAATATGTTTTTCAAGATGTAGTTCATTATCATCTTT 1677 coli GTCATCAGCTGAAGATG AAATAGGATGTAATCAGACGACACA Glu1286TermGGAAGCAGATTCTGCTAATACCCTGCAAATAGCAG GAA-TAACTGCTATTTGCAGGGTATTAGCAGAATCTGCTTCCTGTGTCGT 1678 CTGATTACATCCTATTT CATCTTCAGCTGATGACAAAGATGATA ATGAACTACATCTTGAAAAACATATTGGAGTATC CTGAAGAT GAAATAGGA 1679 TCCTATTT C ATCTTCAG 1680 Adenomatous polyposisTGTAGTTCATTATCATCTTTGTCATCAGCTGAAGATGAAATAGG 1681 coli ATGTAATCAGACGACAC AGGAAGCAGATTCTGCTAATACCCTG Gln1294TermCAAATAGCAGAAATAAAAGAAAAGATTGGAACTA CAG-TAGTAGTTCCAATCTTTTCTTTTATTTCTGCTATTTGCAGGGTATTA 1682 GCAGAATCTGCTTCCT GTGTCGTCTGATTACATCCTATTTCAT CTTCAGCTGATGACAAAGATGATAATGAACTACAAGACGACACAGGAAGCA 1683 TGCTTCCT G TGTCGTCT 1684 Predisposition to,TAGGATGTAATCAGACGACACAGGAAGCAGATTCTGCTAATAC 1685 association with,CCTGCAAATAGCAGAAA T AAAAGAAAAGATTGGAACTAGGTCA colorectal cancerGCTGAAGATCCTGTGAGCGAAGTTCCAGCAGTGTC Ile1307LysGACACTGCTGGAACTTCGCTCACAGGATCTTCAGCTGACCTA 1686 ATA-AAAGTTCCAATCTTTTCTTTT A TTTCTGCTATTTGCAGGGTATTAGCAGAATCTGCTTCCTGTGTCGTCTGATTACATCCTA AGCAGAAA T AAAAGAAA 1687 TTTCTTTT ATTTCTGCT 1688 Adenomatous polyposisCCAAGAAACAATACAGACTTATTGTGTAGAAGATACTCCAATA 1689 coli TGTTTTTCAAGATGTAGT TCATTATCATCTTTGTCATCAGCTGA Glu1309TermAGATGAAATAGGATGTAATCAGACGACACAGGAA GAA-TAATTCCTGTGTCGTCTGATTACATCCTATTTCATCTTCAGCTGATG 1690 ACAAAGATGATAATGA ACTACATCTTGAAAAACATATTGGAGTA TCTTCTACACAATAAGTCTGTATTGTTTCTTGG AGATGTAG TTCATTATC 1691 GATAATGA A CTACATCT 1692 Predisposition toGATTCTGCTAATACCCTGCAAATAGCAGAAATAAAAGAAAAGA 1693 Colorectal CancerTTGGAACTAGGTCAGCT G AAGATCCTGTGAGCGAAGTTCCAG Glu1317GlnCAGTGTCACAGCACCCTAGAACCAAATCCAGCAGAC GAA-CAAGTCTGCTGGATTTGGTTCTAGGGTGCTGTGACACTGCTGGAA 1694 CTTCGCTCACAGGATCTT CAGCTGACCTAGTTCCAATCTTTTC TTTTATTTCTGCTATTTGCAGGGTATTAGCAGAATC GGTCAGCT GAAGATCCT 1695 AGGATCTT C AGCTGACC 1696 Adenomatous polyposisAAAGAAAAGATTGGAACTAGGTCAGCTGAAGATCCTGTGAGC 1697 coli GAAGTTCCAGCAGTGTCAC AGCACCCTAGAACCAAATCCAGC Gln1328TermAGACTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCA CAG-TAGTGGCTGATTCTGAAGATAAACTAGAACCCTGCAGTCTGCTGG 1698 ATTTGGTTCTAGGGTGCT GTGACACTGCTGGAACTTCGCTCA CAGGATCTTCAGCTGACCTAGTTCCAATCTTTTCTTT CAGTGTCA CAGCACCCT 1699 AGGGTGCT G TGACACTG 1700 Adenomatous polyposisGATCCTGTGAGCGAAGTTCCAGCAGTGTCACAGCACCCTAGA 1701 coli ACCAAATCCAGCAGACTGC AGGGTTCTAGTTTATCTTCAGAAT Gln1338TermCAGCCAGGCACAAAGCTGTTGAATTTTCTTCAGGAG CAG-TAGCTCCTGAAGAAAATTCAACAGCTTTGTGCCTGGCTGATTCTGA 1702 AGATAAACTAGAACCCT GCAGTCTGCTGGATTTGGTTCTAGG GTGCTGTGACACTGCTGGAACTTCGCTCACAGGATC GCAGACTG CAGGGTTCT 1703 AGAACCCT G CAGTCTGC 1704 Adenomatous polyposisAAGTTCCAGCAGTGTCACAGCACCCTAGAACCAAATCCAGCA 1705 coli GACTGCAGGGTTCTAGTTT ATCTTCAGAATCAGCCAGGCACAA Leu1342TermAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTC TTA-TAAGAGGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTTGTGC 1706 CTGGCTGATTCTGAAGAT AAACTAGAACCCTGCAGTCTGCTG GATTTGGTTCTAGGGTGCTGTGACACTGCTGGAACTT TTCTAGTT TATCTTCAG 1707 CTGAAGAT A AACTAGAA 1708 Adenomatous polyposisCAGCACCCTAGAACCAAATCCAGCAGACTGCAGGGTTCTAGT 1709 coli TTATCTTCAGAATCAGCCA GGCACAAAGCTGTTGAATTTTCTT Arg1348TrpCAGGAGCGAAATCTCCCTCCCGAAAGTGGTGCTCAG AGG-TGGCTGAGCACCACTTTCGGGAGGGAGATTTCGCTCCTGAAGAAA 1710 ATTCAACAGCTTTGTGCC TGGCTGATTCTGAAGATAAACTAGA ACCCTGCAGTCTGCTGGATTTGGTTCTAGGGTGCTG AATCAGCC AGGCACAAA 1711 TTTGTGCC T GGCTGATT 1712 Adenomatous polyposisCTGCAGGGTTCTAGTTTATCTTCAGAATCAGCCAGGCACAAAG 1713 coli CTGTTGAATTTTCTTCAG GAGCGAAATCTCCCTCCCGAAAGTG Gly1357TermGTGCTCAGACACCCCAAAGTCCACCTGAACACTAT GGA-TGAATAGTGTTCAGGTGGACTTTGGGGTGTCTGAGCACCACTTTC 1714 GGGAGGGAGATTTCGCTC CTGAAGAAAATTCAACAGCTTTGT GCCTGGCTGATTCTGAAGATAAACTAGAACCCTGCAG TTTCTTCA GGAGCGAAA 1715 TTTCGCTC C TGAAGAAA 1716 Adenomatous polyposisCCAGGCACAAAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCC 1717 coli CTCCCGAAAGTGGTGCTC AGACACCCCAAAGTCCACCTGAAC Gln1367TermACTATGTTCAGGAGACCCCACTCATGTTTAGCAGAT CAG-TAGATCTGCTAAACATGAGTGGGGTCTCCTGAACATAGTGTTCAG 1718 GTGGACTTTGGGGTGTCT GAGCACCACTTTCGGGAGGGAGAT TTCGCTCCTGAAGAAAATTCAACAGCTTTGTGCCTGG GTGGTGCT CAGACACCC 1719 GGGTGTCT G AGCACCAC 1720 Adenomatous polyposisAAAGCTGTTGAATTTTCTTCAGGAGCGAAATCTCCCTCCAAAA 1721 coli GTGGTGCTCAGACACCCA AAAGTCCACCTGAACACTATGTTC Lys1370TermAGGAGACCCCACTCATGTTTAGCAGATGTACTTCTG AAA-TAACAGAAGTACATCTGCTAAACATGAGTGGGGTCTCCTGAACATA 1722 GTGTTCAGGTGGACTTT TGGGTGTCTGAGCACCACTTTTGGA GGGAGATTTCGCTCCTGAAGAAAATTCAACAGCTTT AGACACCC AAAAGTCCA 1723 TGGACTTT T GGGTGTCT 1724 Adenomatous polyposisCACCTGAACACTATGTTCAGGAGACCCCACTCATGTTTAGCA 1725 coli GATGTACTTCTGTCAGTTC ACTTGATAGTTTTGAGAGTCGTTC Ser1392TermGATTGCCAGCTCCGTTCAGAGTGAACCATGCAGTGG TCA-TAACCACTGCATGGTTCACTCTGAACGGAGCTGGCAATCGAACGA 1726 CTCTCAAAACTATCAAGT GAACTGACAGAAGTACATCTGCTAA ACATGAGTGGGGTCTCCTGAACATAGTGTTCAGGTG TGTCAGTT CACTTGATA 1727 TATCAAGT G AACTGACA 1728 Adenomatous polyposisCACCTGAACACTATGTTCAGGAGACCCCACTCATGTTTAGCA 1729 coli GATGTACTTCTGTCAGTTC ACTTGATAGTTTTGAGAGTCGTTC Ser1392TermGATTGCCAGCTCCGTTCAGAGTGAACCATGCAGTGG TCA-TGACCACTGCATGGTTCACTCTGAACGGAGCTGGCAATCGAACGA 1730 CTCTCAAAACTATCAAGT GAACTGACAGAAGTACATCTGCTAA ACATGAGTGGGGTCTCCTGAACATAGTGTTCAGGTG TGTCAGTT CATTTGATA 1731 TATCAAGT G AACTGACA 1732 Adenomatous polyposisGTTCAGGAGACCCCACTCATGTTTAGCAGATGTACTTCTGTCA 1733 coli GTTCACTTGATAGTTTTG AGAGTCGTTCGATTGCCAGCTCCGT Glu1397TermTCAGAGTGAACCATGCAGTGGAATGGTAGGTGGCA GAG-TAGTGCCACCTACCATTCCACTGCATGGTTCACTCTGAACGGAGC 1734 TGGCAATCGAACGACTCT CAAAACTATCAAGTGAACTGACAGA AGTACATCTGCTAAACATGAGTGGGGTCTCCTGAAC ATAGTTTT GAGAGTCGT 1735 ACGACTCT C AAAACTAT 1736 Adenomatous polyposisCAAACCATGCCACCAAGCAGAAGTAAAACACCTCCACCACCT 1737 coli CCTCAAACAGCTCAAACCA AGCGAGAAGTACCTAAAAATAAAG Lys1449TermCACCTACTGCTGAAAAGAGAGAGAGTGGACCTAAGC AAG-TAGGCTTAGGTCCACTCTCTCTCTTTTCAGCAGTAGGTGCTTTATT 1738 TTTAGGTACTTCTCGCT TGGTTTGAGCTGTTTGAGGAGGTGGT GGAGGTGTTTTACTTCTGCTTGGTGGCATGGTTTG CTCAAACC AAGCGAGAA 1739 TTCTCGCT T GGTTTGAG 1740 Adenomatous polyposisACCATGCCACCAAGCAGAAGTAAAACACCTCCACCACCTCCT 1741 coli CAAACAGCTCAAACCAAGC GAGAAGTACCTAAAAATAAAGCAC Arg1450TermCTACTGCTGAAAAGAGAGAGAGTGGACCTAAGCAAG CGA-TGACTTGCTTAGGTCCACTCTCTCTCTTTTCAGCAGTAGGTGCTTT 1742 ATTTTTAGGTACTTCTC GCTTGGTTTGAGCTGTTTGAGGAGGT GGTGGAGGTGTTTTACTTCTGCTTGGTGGCATGGT AAACCAAG CGAGAAGTA 1743 TACTTCTC G CTTGGTTT 1744 Adenomatous polyposisCAGATGCTGATACTTTATTACATTTTGCCACGGAAAGTACTCC 1745 coli AGATGGATTTTCTTGTTC ATCCAGCCTGAGTGCTCTGAGCCTC Ser1503TermGATGAGCCATTTATACAGAAAGATGTGGAATTAAG TCA-TAACTTAATTCCACATCTTTCTGTATAAATGGCTCATCGAGGCTCA 1746 GAGCACTCAGGCTGGAT GAACAAGAAAATCCATCTGGAGTAC TTTCCGTGGCAAAATGTAATATAAGTATCAGCATCTG TTCTTGTTC ATCCAGCC 1747 GGCTGGAT G AACAAGAA 1748 Adenomatous polyposisCTGAGCCTCGATGAGCCATTTATACAGAAAGATGTGGAATTAA 1749 coli GAATAATGCCTCCAGTTC AGGAAAATGACAATGGGAATGAAAC Gln1529TermAGAATCAGAGCAGCCTAAAGAATCAAATGAAAACC CAG-TAGGGTTTTCATTTGATTCTTTAGGCTGCTCTGATTCTGTTTCATTC 1750 CCATTGTCATTTTCCT GAACTGGAGGCATTATTCTTAATTCCAC ATCTTTCTGTATAAATGGCTCATCGAGGCTCAG CTCCAGTT CAGGAAAAT 1751 ATTTTCCT G AACTGGAG 1752 Adenomatous polyposisATGTGGAATTAAGAATAATGCCTCCAGTTCAGGAAAATGACAA 1753 coli TGGGAATGAAACAGAATC AGAGCAGCCTAAAGAATCAAATGAA Ser1539TermAACCAAGAGAAAGAGGCAGAAAAAACTATTGATTC TCA-TAAGAATCAATAGTTTTTTCTGCCTCTTTCTCTTGGTTTTCATTTGA 1754 TTCTTTAGGCTGCTCT GATTCTGTTTCATTCCCATTGTCATTTT CCTGAACTGGAGGCATTATTCTTAATTCCACAT AACAGAAT CAGAGCAGC 1755 GCTGCTCT G ATTCTGTT 1756 Adenomatous polyposisAAAACCAAGAGAAAGAGGCAGAAAAAACTATTGATTCTGAAAA 1757 coli GGACCTATTAGATGATTC AGATGATGATGATATTGAAATACTA Ser1567TermGAAGAATGTATTATTTCTGCCATGCCAACAAAGTC TCA-TGAGACTTTGTTGGCATGGCAGAAATAATACATTCTTCTAGTATTTC 1758 AATATCATCATCATCT GAATCATCTAATAGGTCCTTTTCAGAAT CAATAGTTTTTTCTGCCTCTTTCTCTTGGTTTT AGATGATT CAGATGATG 1759 CATCATCT G AATCATCT 1760 Adenomatous polyposisAGAGAGTTTTCTCAGACAACAAAGATTCAAAGAAACAGAATTT 1761 coli GAAAAATAATTCCAAGGA CTTCAATGATAAGCTCCCAAATAAT Asp18222ValGAAGATAGAGTCAGAGGAAGTTTTGCTTTTGATTC GAC-GTCGAATCAAAAGCAAAACTTCCTCTGACTCTATCTTCATTATTTGG 1762 GAGCTTATCATTGAAG TCCTTGGAATTATTTTTCAAATTCTGTT TCTTTGAATCTTTGTTGTCTGAGAAAACTCTCT TTCCAAGG ACTTCAATG 1763 CATTGAAG T CCTTGGAA 1764 Adenomatous polyposisAAAACTGACAGCACAGAATCCAGTGGAACAAAGTCCTAAG 1765 coli CGCCATTCTGGGTCTTAC CTTGTGACATCTGTTTAAAAGAGAG Leu2839Phe GAAGAATGAAACTAAGAAAATTCTATGTTAATTACACTT-TTT TGTAATTAACATAGAATTTTCTTAGTTTCATTCTTCCTCTCTTTT 1766AAACAGATGTCACAA G GTAAGACCCAGAATGGCGCTTAGGACTTTGGGTTCCACTGGATTCTGTGCTGTCAGTTTT GGTCTTAC C TTGTGACA 1767TGTCACAAGGTAAGACC 1768

EXAMPLE 12 Parahemophilia—Factor V Deficiency

[0133] Deficiency in clotting Factor V is associated with a lifelongpredisposition to thrombosis. The disease typically manifests itselfwith usually mild bleeding, although bleeding times and clotting timesare consistently prolonged. Individuals that are heterozygous for amutation in Factor V have lowered levels of factor V but probably neverhave abnormal bleeding. A large number of alleles with a range ofpresenting symptoms have been identified. The attached table disclosesthe correcting oligonucleotide base sequences for the Factor Voligonucleotides of the invention. TABLE 19 Factor V Mutations andGenome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation CorrectingOligos NO: Factor V deficiencyTTGACTGAATGCTTATTTTGGCCTGTGTCTCTCCCTCTTTCTCA 1768 Ala221ValGATATAACAGTTTGTG C CCATGACCACATCAGCTGGCATCTGC GCC-GTCTGGGAATGAGCTCGGGGCCAGAATTATTCTCCATATGGAGAATAATTCTGGCCCCGAGCTCATTCCCAGCAGATGC 1769 CAGCTGATGTGGTCATGG GCACAAACTGTTATATCTGAGAAAG AGGGAGAGACACAGGCCAAAATAAGCATTCAGTCAA AGTTTGTG CCCATGACC 1770 GGTCATGG G CACAAACT 1771 ThrombosisTGTCCTAACTCAGCTGGGATGCAGGCTTACATTGACATTAAAA 1772 Arg306GlyACTGCCCAAAGAAAACC A GGAATCTTAAGAAAATAACTCGTGA AGG-GGGGCAGAGGCGGCACATGAAGAGGTGGGAATACTTCATGAAGTATTCCCACCTCTTCATGTGCCGCCTCTGCTCACGAGT 1773 TATTTTCTTAAGATTCC TGGTTTTCTTTGGGCAGTTTTTAATGT CAATGTAAGCCTGCATCCCAGCTGAGTTAGGACA AGAAAACC AGGAATCTT 1774 AAGATTCC T GGTTTTCT 1775 ThrombosisGTCCTAACTCAGCTGGGATGCAGGCTTACATTGACATTAAAAA 1776 Arg306ThrCTGCCCAAAGAAAACCA G GAATCTTAAGAAAATAACTCGTGAG AGG-ACGCAGAGGCGGCACATGAAGAGGTGGGAATACTTCATATGAAGTATTCCCACCTCTTCATGTGCCGCCTCTGCTCACGA 1777 GTTATTTTCTTAAGATTC CTGGTTTTCTTTGGGCAGTTTTTAAT GTCAATGTAAGCCTGCATCCCAGCTGAGTTAGGAC GAAAACCA GGAATCTTA 1778 TAAGATTC C TGGTTTTC 1779 Increased RiskCCACAGAAAATGATGCCCAGTGCTTAACAAGACCATACTACAG 1780 ThrombosisTGACGTGGACATCATGA G AGACATCGCCTCTGGGCTAATAGG Arg485LysACTACTTCTAATCTGTAAGAGCAGATCCCTGGACAG AGA-AAACTGTCCAGGGATCTGCTCTTACAGATTAGAAGTAGTCCTATTA 1781 GCCCAGAGGCGATGTCT CTCATGATGTCCACGTCACTGTAGT ATGGTCTTGTTAAGCACTGGGCATCATTTTCTGTGG CATCATGA GAGACATCG 1782 CGATGTCT C TCATGATG 1783 Increased RiskACATCGCCTCTGGGCTAATAGGACTACTTCTAATCTGTAAGAG 1784 ThrombosisCAGATCCCTGGACAGGC G AGGAATACAGGTATTTTGTCCTTG Arg506GlnAAGTAACCTTTCAGAAATTCTGAGAATTTCTTCTGG CGA-CAACCAGAAGAAATCTCAGAATTCTGAAAGGTTACTTCAAGGAC 1785 AAAATACCTGTATTCCT CGCCTGTCCAGGGATCTGCTCTTACA GATTAGAAGTAGTCCTATTAGCCCAGAGGCGATGT GGACAGGC GAGGAATAC 1786 GTATTCCT C GCCTGTCC 1787 Factor V DeficiencyGACATCGCCTCTGGGCTAATAGGACTACTTCTAATCTGTAAGA 1788 Arg506TermGCAGATCCCTGGACAGG C GAGGAATACAGGTATTTTGTCCTT CGA-TGAGAAGTAACCTTTCAGAAATTCTGAGAATTTCTTCTGCAGAAGAAATTCTCAGAATTTCTGAAAGGTTACTTCAAGGACA 1789 AAATACCTGTATTCCTC GCCTGTCCAGGGATCTGCTCTTACAG ATTAGAAGTAGTCCTATTAGCCCAGAGGCGATGTC TGGACAGG CGAGGAATA 1790 TATTCCTC G CCTGTCCA 1791 ThrombosisAGTGATGCTGACTATGATTACCAGAACAGACTGGCTGCAGCA 1792 Arg712TermTTAGGAATCAGGTCATTC C GAAACTCATCATTGAATCAGGAAG CGA-TGAAAGAAGAGTTCAATCTTACTGCCCTAGCTCTGGAGATCTCCAGAGCTAGGGCAGTAAGATTGAACTCTTCTTCTTCCTG 1793 ATTCAATGATGAGTTTC GGAATGACCTGATTCCTAATGCTGCA GCCAGTCTGTTCTGGTAATCATAGTCAGCATCACT GGTCATTC CGAAACTCA 1794 TGAGTTTC G GAATGACC 1795 ThrombosisTCAGTCAGACAAACCTTTCCCCAGCCCTCGGTCAGATGCCCA 1796 His1299ArgTTTCTCCAGACCTCAGCC A TACAACCCTTTCTCTAGACTTCAG CAT-CGTCCAGACAAACCTCTCTCCAGAACTCAGTCAAACAAATTTGTTTGACTGAGTTCTGGAGAGAGGTTTGTCTGGCTGAAGT 1797 CTAGAGAAAGGGTTGTA TGGCTGAGGTCTGGAGAAATGGGCA TCTGACCGAGGGCTGGGGAAAGGTTTGTCTGACTGA CCTCAGCC ATACAACCC 1798 GGGTTGTA T GGCTGAGG 1799

EXAMPLE 13 Hemophilia—Factor VIII Deficiency

[0134] The attached table discloses the correcting oligonucleotide basesequences for the Factor VIII oligonucleotides of the invention. TABLE20 Factor VIII Mutations and Genome-Correcting Oligos Clinical Phenotype& SEQ ID Mutation Correcting Oligos NO: Haemophilia AAGCTCTCCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTT 1800 Tyr5CysTAGTGCCACCAGAAGAT A CTACCTGGGTGCAGTGGAACTGTC TAC-TGCATGGGACTATATGCAAAGTGATCTCGGTGAGCTGCCGGCAGCTCACCGAGATCACTTTGCATATAGTCCCATGACAGT 1801 TCCACTGCACCCAGGTAG TATCTTCTGGTGGCACTAAAGCAG AATCGCAAAAGGCACAGAAAGAAGCAGGTGGAGAGCT CAGAAGAT ACTACCTGG 1802 CCAGGTAG T ATCTTCTG 1803 Haemophilia ACCACCTGCTTCTTTCTGTGCCTTTTGCGATTCTGCTTTAGTGC 1804 Leu7ArgCACCAGAAGATACTACC T GGGTGCAGTGGAACTGTCATGGGA CTG-CGGCTATATGCAAAGTGATCTCGGTGAGCTGCCTGTGGATCCACAGGCAGCTCACCGAGATCACTTTGCATATAGTCCCAT 1805 GACAGTTCCACTGCACCC AGGTAGTATCTTCTGGTGGCACTA AAGCAGAATCGCAAAAGGCACAGAAAGAAGCAGGTGG ATACTACC TGGGTGCAG 1806 CTGCACCC A GGTAGTAT 1807 Haemophilia AAGTCATGCAAATAGAGCTCTCCACCTGCTTCTTTCTGTGCCTT 1808 Ser(−1)ArgTTGCGATTCTGCTTTAG T GCCACCAGAAGATACTACCTGGGT AGTg-AGGGCAGTGGAACTGTCATGGGACTATATGCAAAGTGATATCACTTTGCATATAGTCCCATGACAGTTCCACTGCACCCAG 1809 GTAGTATCTTCTGGTGGC ACTAAAGCAGAATCGCAAAAGGCA CAGAAAGAAGCAGGTGGAGAGCTCTATTTGCATGACT TGCTTTAG TGCCACCAG 1810 CTGGTGGC A CTAAAGCA 1811 Haemophilia ACATTTGTAGCAATAAGTCATGCAAATAGAGCTCTCCACCTGCT 1812 Arg(−5)TermTCTTTCTGTGCCTTTTG C GATTCTGCTTTAGTGCCACCAGAAG gCGA-TGAATACTACCTGGGTGCAGTGGAACTGTCATGGGACTAGTCCCATGACAGTTCCACTGCACCCAGGTAGTATCTTCTGG 1813 TGGCACTAAAGCAGAATC GCAAAAGGCACAGAAAGAAGCAGG TGGAGAGCTCTATTTGCATGACTTATTGCTACAAATG GCCTTTTG CGATTCTGC 1814 GCAGAATC G CAAAAGGC 1815 Haemophilia ATTCTGTGCCTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATA 1816 Glu11ValCTACCTGGGTGCAGTGG A ACTGTCATGGGACTATATGCAAAG GAA-GTATGATCTCGGTGAGCTGCCTGTGGACGCAAGGTAAAGCTTTACCTTGCGTCCACAGGCAGCTCACCGAGATCACTTTGC 1817 ATATAGTCCCATGACAGT TCCACTGCACCCAGGTAGTATCTTC TGGTGGCACTAAAGCAGAATCGCAAAAGGCACAGAA TGCAGTGG AACTGTCAT 1818 ATGACAGT T CCACTGCA 1819 Haemophilia ACTTTTGCGATTCTGCTTTAGTGCCACCAGAAGATACTACCTGG 1820 Trp14GlyGTGCAGTGGAACTGTCA T GGGACTATATGCAAAGTGATCTCG aTGG-GGGGTGAGCTGCCTGTGGACGCAAGGTAAAGGCATGTCCGGACATGCCTTTACCTTGCGTCCACAGGCAGCTCACCGAGAT 1821 CACTTTGCATATAGTCCC ATGACAGTTCCACTGCACCCAGGT AGTATCTTCTGGTGGCACTAAAGCAGAATCGCAAAAG AACTGTCA TGGGACTAT 1822 ATAGTCCC A TGACAGTT 1823 Haemophilia ATTCACGCAGATTTCCTCCTAGAGTGCCAAAATCTTTTCCATTC 1824 Tyr46TermAACACCTCAGTCGTGTA C AAAAAGACTCTGTTTGTAGAATTCA TACa-TAACGGATCACCTTTTCAACATCGCTAAGCCAAGGCCATGGCCTTGGCTTAGCGATGTTGAAAAGGTGATCCGTGAATTC 1825 TACAAACAGAGTCTTTTT GTACACGACTGAGGTGTTGAATGGA AAAGATTTTGGCACTCTAGGAGGAAATCTGCGTGAA GTCGTGTA CAAAAAGAC 1826 GTCTTTTT G TACACGAC 1827 Haemophilia AATCTTTTCCATTCAACACCTCAGTCGTGTACAAAAAGACTCTG 1828 Asp56GluTTTGTAGAATTCACGGA T CACCTTTTCAACATCGCTAAGCCAA I GATc-GAAGGCCACCCTGGATGGGTAATGAAAACAATGTTGAATTCAACATTGTTTTCATTACCCATCCAGGGTGGCCTTGGCTTA 1829 GCGATGTTGAAAAGGTG ATCCGTGAATTCTACAAACAGAGTC TTTTGTACACGACTGAGGTGTTGAATGGAAAAGAT TTCACGGA TCACCTTTT 1830 AAAAGGTG A TCCGTGAA 1831 Haemophilia ATTCTGGAGTACTATCCCCAAGTAACCTTTGGCGGACATCTCAT 1832 Gly73ValTCTTACAGGTCTGCTAG G TCCTACCATCCAGGCTGAGGTTTA GGT-GTTTGATACAGTGGTCATTACACTTAAGAACATGGCTTCGAAGCCATGTTCTTAAGTGTAATGACCACTGTATCATAAACCT 1833 CAGCCTGGATGGTAGGA CCTAGCAGACCTGTAAGAATGAGAT GTCCGCCAAAGGTTACTTGGGGATAGTACTCCAGAA TCTGCTAG GTCCTACCA 1834 TGGTAGGA C CTAGCAGA 1835 Haemophiiia ACAAGTAACCTTTGGCGGACATCTCATTCTTACAGGTCTGCTAG 1836 Glu79LysGTCCTACCATCCAGGCT G AGGTTTATGATACAGTGGTCATTAC tGAG-AAGACTTAAGAACATGGCTTCCCATCCTGTCAGTCTTCGAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTAATGA 1837 CCACTGTATCATAAACCT CAGCCTGGATGGTAGGACCTAGCA GACCTGTAAGAATGAGATGTCCGCCAAAGGTTACTTG TCCAGGCT GAGGTTTAT 1838 ATAAACCT C AGCCTGGA 1839 Haemophilia ATAACCTTTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCC 1840 Val80AspTACCATCCAGGCTGAGG T TTATGATACAGTGGTCATTACACTT GTT-GATAAGAACATGGCTTCCCATCCTGTCAGTCTTCATGCGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTAAGTGTA 1841 ATGACCACTGTATCATAA ACCTCAGCCTGGATGGTAGGACCT AGCAGACCTGTAAGAATGAGATGTCCGCCAAAGGTTA GGCTGAGG TTTATGATA 1842 TATCATAA A CCTCAGCC 1843 Haemophilia ATTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCCTACCAT 1844 Asp82ValCCAGGCTGAGGTTTATG A TACAGTGGTCATTACACTTAAGAAC GAT-GTTATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGGCCAACAGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTA 1845 AGTGTAATGACCACTGTA TCATAAACCTCAGCCTGGATGGTA GGACCTAGCAGACCTGTAAGAATGAGATGTCCGCCAA GGTTTATG ATACAGTGG 1846 CCACTGTA T CATAAACC 1847 Haemophilia ATTGGCGGACATCTCATTCTTACAGGTCTGCTAGGTCCTACCAT 1848 Asp82GlyCCAGGCTGAGGTTTATG A TACAGTGGTCATTACACTTAAGAAC GAT-GGTATGGCTTCCCATCCTGTCAGTCTTCATGCTGTTGGCCAACAGCATGAAGACTGACAGGATGGGAAGCCATGTTCTTA 1849 AGTGTAATGACCACTGTA TCATAAACCTCAGCCTGGATGGTA GGACCTAGCAGACCTGTAAGAATGAGATGTCCGCCAA GGTTTATG ATACAGTGG 1850 CCACTGTA T CATAAACC 1851 Haemophilia AATCTCATTCTTACAGGTCTGCTAGGTCCTACCATCCAGGCTGA 1852 Val85AspGGTTTATGATACAGTGG T CATTACACTTAAGAACATGGCTTCC GTC-GACCATCCTGTCAGTCTTCATGCTGTTGGTGTATCCTATAGGATACACCAACAGCATGAAGACTGACAGGATGGGAAGCC 1853 ATGTTCTTAAGTGTAAT GACCACTGTATCATAAACCTCAGCCT GGATGGTAGGACCTAGCAGACCTGTAAGAATGAGAT TACAGTGGT CATTACAC 1854 GTGTAATG A CCACTGTA 1855 Haemophilia ACAGGTCTGCTAGGTCCTACCATCCAGGCTGAGGTTTATGATA 1856 Lys89ThrCAGTGGTCATTACACTTA A GAACATGGCTTCCCATCCTGTCA AAG-ACGGTCTTCATGCTGTTGGTGTATCCTACTGGAAAGCTTCGAAGCTTTCCAGTAGGATACACCAACAGCATGAAGACTGACA 1857 GGATGGGAAGCCATGTTC TTAAGTGTAATGACCACTGTATCAT AAACCTCAGCCTGGATGGTAGGACCTAGCAGACCTG TACACTTA AGAACATGG 1858 CCATGTTC T TAAGTGTA 1859 Haemophilia ACTGCTAGGTCCTACCATCCAGGCTGAGGTTTATGATACAGTG 1860 Met91ValGTCATTACACTTAAGAAC A TGGCTTCCCATCCTGTCAGTCTTC cATG-GTGATGCTGTTGGTGTATCCTACTGGAAAGCTTCTGAGGCCTCAGAAGCTTTCCAGTAGGATACACCAACAGCATGAAGAC 1861 TGACAGGATGGGAAGCCA TGTTCTTAAGTGTAATGACCACTG TATCATAAACCTCAGCCTGGATGGTAGGACCTAGCAG TTAAGAAC ATGGCTTCC 1862 GGAAGCCA T GTTCTTAA 1863 Haemophilia ACTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACACT 1864 His94ArgTAAGAACATGGCTTCCC A TCCTGTCAGTCTTCATGCTGTTGGT CAT-CGTGTATCCTACTGGAAAGCTTCTGAGGGTGAGTAAAATTTTACTCACCCTCAGAAGCTTTCCAGTAGGATACACCAACAG 1865 CATGAAGACTGACAGGA TGGGAAGCCATGTTCTTAAGTGTAA TGACCACTGTATCATAAACCTCAGCCTGGATGGTAG GGCTTCCC ATCCTGTCA 1866 TGACAGGA T GGGAAGCC 1867 Haemophilia ACCTACCATCCAGGCTGAGGTTTATGATACAGTGGTCATTACAC 1868 His94TyrTTAAGAACATGGCTTCC C ATCCTGTCAGTCTTCATGCTGTTGG cCAT-TATTGTATCCTACTGGAAAGCTTCTGAGGGTGAGTAAATTTACTCACCCTCAGAAGCTTTCCAGTAGGATACACCAACAGC 1869 ATGAAGACTGACAGGA TGGGAAGCCATGTTCTTAAGTGTAAT GACCACTGTATCATAAACCTCAGCCTGGATGGTAGG TGGCTTCCC ATCCTGTC 1870 GACAGGAT G GGAAGCCA 1871 Haemophilia ACTGAGGTTTATGATACAGTGGTCATTACACTTAAGAACATGGC 1872 Leu98ArgTTCCCATCCTGTCAGTC T TCATGCTGTTGGTGTATCCTACTGG CTT-CGTAAAGCTTCTGAGGGTGAGTAAAATACCCTCCTATTAATAGGAGGGTATTTTACTCACCCTCAGAAGCTTTCCAGTAGG 1873 ATACACCAACAGCATGA AGACTGACAGGATGGGAAGCCATGT TCTTAAGTGTAATGACCACTGTATCATAAACCTCAG TGTCAGTC TTCATGCTG 1874 CAGCATGA A GACTGACA 1875 Haemophilia AGATACAGTGGTCATTACACTTAAGAACATGGCTTCCCATCCTG 1876 Gly102SerTCAGTCTTCATGCTGTT G GTGTATCCTACTGGAAAGCTTCTGA tGGT-AGTGGGTGAGTAAAATACCCTCCTATTGTCCTGTCATTAATGACAGGACAATAGGAGGGTATTTTACTCACCCTCAGAAG 1877 CTTTCCAGTAGGATACAC CAACAGCATGAAGACTGACAGGAT GGGAAGCCATGTTCTTAAGTGTAATGACCACTGTATC ATGCTGTT GGTGTATCC 1878 GGATACAC C AACAGCAT 1879 Haemophilia ACTTTGAGTGTACAGTGGATATAGAAAGGACAATTTTATTTCTTC 1880 Glu113AspCTGCTATAGGAGCTGA A TATGATGATCAGACCAGTCAAAGGG GAAt-GACAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGA 1881 CTGGTCTGATCATCATA TTCAGCTCCTATAGCAGGAAGAAATA AAATTGTCCTTTCTATATCCACTGTACACTCAAAG GGAGCTGA ATATGATGA 1882 TCATCATA T TCAGCTCC 1883 Haemophilia ATTGAGTGTACAGTGGATATAGAAAGGACAATTTTATTTCTTCCT 1884 Tyr114CysGCTATAGGAGCTGAAT A TGATGATCAGACCAGTCAAAGGGAG TAT-TGTAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCCATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTT 1885 GACTGGTCTGATCATCA TATTCAGCTCCTATAGCAGGAAGAAA TAAAATTGTCCTTTCTATATCCACTGTACACTCAA AGCTGAAT ATGATGATC 1886 GATCATCA T ATTCAGCT 1887 Haemophilia AGTACAGTGGATATAGAAAGGACAATTTTATTCTTCCTGCTATA 1888 Asp116GlyGGAGCTGAATATGATG A TCAGACCAGTCAAAGGGAGAAAGAA GAT-GGTGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTTCT 1889 CCCTTTGACTGGTCTGA TCATCATATTCAGCTCCTATAGCAGG AAGAAATAAAATTGTCCTTTCTATATCCACTGTAC ATATGATG ATCAGACCA 1890 TGGTCTGA T CATCATAT 1891 Haemophilia AACAGTGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATAG 1892 Gln117TermGAGCTGAATATGATGAT C AGACCAGTCAAAGGGAGAAAGAAG tCAG-TAGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGCATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTTCTTT 1893 CTCCCTTTGACTGGTCT GATCATCATATTCAGCTCCTATAGCA GGAAGAAATAAAATTGTCCTTTCTATATCCACTGT ATGATGAT CAGACCAGT 1894 ACTGGTCT G ATCATCAT 1895 Haemophilia ATGGATATAGAAAGGACAATTTTATTTCTTCCTGCTATAGGAGC 1896 Thr118IleTGAATATGATGATCAGA C CAGTCAAAGGGAGAAAGAAGATGA ACC-ATCTAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGCAGACATATGTATGGCTTCCACCAGGGAAGACTTTATCATCTT 1897 CTTTCTCCCTTTGACTG GTCTGATCATCATATTCAGCTCCTAT AGCAGGAAGAAATAAAATTGTCCTTTCTATATCCA TGATCAGA CCAGTCAAA 1898 TTTGACTG G TCTGATCA 1899 Haemophilia AAGGACAATTTTATTTCTTCCTGCTATAGGAGCTGAATATGATG 1900 Glu122TermATCAGACCAGTCAAAGG G AGAAAGAAGATGATAAAGTCTTCC gGAG-TAGCTGGTGGAAGCCATACATATGTCTGGCAGGTCCTGATCAGGACCTGCCAGACATATGTATGGCTTCCACCAGGGAAGA 1901 CTTTATCATCTTCTTTCT CCCTTTGACTGGTCTGATCATCATAT TCAGCTCCTATAGCAGGAAGAAATAAAATTGTCCT GTCAAAGG GAGAAAGAA 1902 TTCTTTCT C CCTTTGAC 1903 Haemophilia ATTTCTTCCTGCTATAGGAGCTGAATATGATGATCAGACCAGTC 1904 Asp126HisAAAGGGAGAAAGAAGAT G ATAAAGTCTTCCCTGGTGGAAGCC tGAT-CATATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTCGACCATTCTCTTTCAGGACCTGCCAGACATATGTATGGCTTCC 1905 ACCAGGGAAGACTTTAT CATCTTCTTTCTCCCTTTGACTGGTC TGATCATCATATTCAGCTCCTATAGCAGGAAGAAA AAGAAGAT GATAAAGTC 1906 GACTTTAT C ATCTTCTT 1907 Haemophilia AAGTCAAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGA 1908 Gln139TermAGCCATACATATGTCTGG C AGGTCCTGAAAGAGAATGGTCCA gCAG-TAGATGGCCTCTGACCCACTGTGCCTTACCTACTCATATCGATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTGGA 1909 CCATTCTCTTTCAGGACCT GCCAGACATATGTATGGCTTCCAC CAGGGAAGACTTTATCATCTTCTTTCTCCCTTTGACT ATGTCTGG CAGGTCCTG 1910 CAGGACCT G CCAGACAT 1911 Haemophilia AAAAGGGAGAAAGAAGATGATAAAGTCTTCCCTGGTGGAAGCC 1912 Val140AlaATACATATGTCTGGCAGG T CCTGAAAGAGAATGGTCCAATGG GTC-GCCCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTCGAAAGATATGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATT 1913 GGACCATTCTCTTTCAGG ACCTGCCAGACATATGTATGGCTT CCACCAGGGAAGACTTTATCATCTTCTTTCTCCCTTT CTGGCAGG TCCTGAAAG 1914 CTTTCAGG A CCTGCCAG 1915 Haemophilia AAGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTG 1916 Asn144LysGCAGGTCCTGAAAGAGAA T GGTCCAATGGCCTCTGACCCACT AATg-AAAGTGCCTTACCTACTCATATCTTTCTCATGTGGACCTGCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGTGG 1917 GTCAGAGGCCATTGGACC ATTCTCTTTCAGGACCTGCCAGAC ATATGTATGGCTTCCACCAGGGAAGACTTTATCATCT AAAGAGAA TGGTCCAAT 1918 ATTGGACC A TTCTCTTT 1919 Haemophilia AGATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCA 1920 Gly145AspGGTCCTGAAAGAGAATG G TCCAATGGCCTCTGACCCACTGTG GGT-GATCCTTACCTACTCATATCTTTCTCATGTGGACCTGGTACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGT 1921 GGGTCAGAGGCCATTGGA CCATTCTCTTTCAGGACCTGCCAG ACATATGTATGGCTTCCACCAGGGAAGACTTTATCAT AGAGAATG GTCCAATGG 1922 CCATTGGA C CATTCTCT 1923 Haemophilia AATGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCA 1924 Gly145ValGGTCCTGAAAGAGAATG G TCCAATGGCCTCTGACCCACTGTG GGT-GTTCCTTACCTACTCATATCTTTCTCATGTGGACCTGGTACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACAGT 1925 GGGTCAGAGGCCATTGGA CCATTCTCTTTCAGGACCTGCCAG ACATATGTATGGCTTCCACCAGGGAAGACTTTATCAT AGAGAATG GTCCAATGG 1926 CCATTGGA C CATTCTCT 1927 Haemophilia AGATAAAGTCTTCCCTGGTGGAAGCCATACATATGTCTGGCAG 1928 Pro146SerGTCCTGAAAGAGAATGGT C CAATGGCCTCTGACCCACTGTGC tCCA-TCACTTACCTACTCATATCTTTCTCATGTGGACCTGGTAATTACCAGGTCCACATGAGAAAGATATGAGTAGGTAAGGCACA 1929 GTGGGTCAGAGGCCATTG GACCATTCTCTTTCAGGACCTGCC AGACATATGTATGGCTTCCACCAGGGAAGACTTTATC AGAATGGT CCAATGGCC 1930 GGCCATTG G ACCATTCT 1931 Haemophilia ACCATACATATGTCTGGCAGGTCCTGAAAGAGAATGGTCCAAT 1932 Cys153TrpGGCCTCTGACCCACTGTG C CTTACCTACTCATATCTTTCTCAT TGCc-TGGGTGGACCTGGTAAAAGACTTGAATTCAGGCCTCATTAATGAGGCCTGAATTCAAGTCTTTTACCAGGTCCACATGAGAA 1933 AGATATGAGTAGGTAAG GCACAGTGGGTCAGAGGCCATTGGA CCATTCTCTTTCAGGACCTGCCAGACATATGTATGG CCACTGTG CCTTACCTA 1934 TAGGTAAG G CACAGTGG 1935 Haemophilia ATGTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGA 1936 Tyr156TermCCCACTGTGCCTTACCTA C TCATATCTTTCTCATGTGGACCTG TACt-TAAGTAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTATAGGGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGTC 1937 CACATGAGAAAGATATGA GTAGGTAAGGCACAGTGGGTCAGA GGCCATTGGACCATTCTCTTTCAGGACCTGCCAGACA CTTACCTA CTCATATCT 1938 AGATATGA G TAGGTAAG 1939 Haemophilia AGTCTGGCAGGTCCTGAAAGAGAATGGTCCAATGGCCTCTGAC 1940 Ser157ProCCACTGTGCCTTACCTAC T CATATCTTTCTCATGTGGACCTGG cTCA-CCATAAAAGACTTGAATTCAGGCCTCATTGGAGCCCTACGTAGGGCTCCAATGAGGCCTGAATTCAAGTCTTTTACCAGGT 1941 CCACATGAGAAAGATATG AGTAGGTAAGGCACAGTGGGTCAG AGGCCATTGGACCATTCTCTTTCAGGACCTGCCAGAC TTACCTAC TCATATCTT 1942 AAGATATG A GTAGGTAA 1943 Haemophilia AGTCCTGAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGC 1944 Ser160ProCTTACCTACTCATATCTT T CTCATGTGGACCTGGTAAAAGACT tTCT-CCTTGAATTCAGGCCTCATTGGAGCCCTACTAGTATGTATACATACTAGTAGGGCTCCAATGAGGCCTGAATTCAAGTCTTT 1945 TACCAGGTCCACATGAG AAAGATATGAGTAGGTAAGGCACAG TGGGTCAGAGGCCATTGGACCATTCTCTTTCAGGAC CATATCTT TCTCATGTG 1946 CACATGAG A AAGATATG 1947 Haemophilia AAAAGAGAATGGTCCAATGGCCTCTGACCCACTGTGCCTTACC 1948 Val162MetTACTCATATCTTTCTCAT G TGGACCTGGTAAAAGACTTGAATT tGTG-ATGCAGGCCTCATTGGAGCCCTACTAGTATGTAGAGAAGCTTCTCTACATACTAGTAGGGCTCCAATGAGGCCTGAATTCAA 1949 GTCTTTTACCAGGTCCA CATGAGAAAGATATGAGTAGGTAAG GCACAGTGGGTCAGAGGCCATTGGACCATTCTCTTT TTTCTCAT GTGGACCTG 1950 CAGGTCCA C ATGAGAAA 1951 Haemophilia ACAATGGCCTCTGACCCACTGTGCCTTACCTACTCATATCTTTC 1952 Lys166ThrTCATGTGGACCTGGTAA A AGACTTGAATTCAGGCCTCATTGG AAA-ACAAGCCCTACTAGTATGTAGAGAAGGTAAGTGTATGAATTCATACACTTACCTTCTCTACATACTAGTAGGGCTCCAATGA 1953 GGCCTGAATTCAAGTCT TTTACCAGGTCCACATGAGAAAGATA TGAGTAGGTAAGGCACAGTGGGTCAGAGGCCATTG CCTGGTAA AAGACTTGA 1954 TCAAGTCT T TTACCAGG 1955 Haemophilia AACCCACTGTGCCTTACCTACTCATATCTTTCTCATGTGGACCT 1956 Ser170LeuGGTAAAAGACTTGAATT C AGGCCTCATTGGAGCCCTACTAGT TCA-TTAATGTAGAGAAGGTAAGTGTATGAAAGCGTAGGATTGCAATCCTACGCTTTCATACACTTACCTTCTCTACATACTAGTAG 1957 GGCTCCAATGAGGCCT GAATTCAAGTCTTTTACCAGGTCCAC ATGAGAAAGATATGAGTAGGTAAGGCACAGTGGGT CTTGAATT CAGGCCTCA 1958 TGAGGCCT G AATTCAAG 1959 Haemophilia AAATGTTCTCACTTCTTTTTCAGGGAGTCTGGCCAAGGAAAAGA 1960 Phe195ValCACAGACCTTGCACAAA T TTATACTACTTTTTGCTGTATTTGAT aTTT-GTTGAAGGTTAGTGAGTCTTAATCTGAATTTTGGATTAATCCAAAATTCAGATTAAGACTCACTAACCTTCATCAAATACA 1961 GCAAAAAGTAGTATAAATTTGTGCAAGGTCTGTGTCTTTTCCT TGGCCAGACTCCCTGAAAAAGAAGTGAGAACATT TGCACAAAT TTATACTA 1962 TAGTATAA A TTTGTGCA 1963 Haemophilia ACTTCTTTTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCT 1964 Leu198HisTGCACAAATTTATACTAC T TTTTGCTGTATTTGATGAAGGTTAG CTT-CATTGAGTCTTAATCTGAATTTTGGATTCCTGAAAGAATTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACTAACCTTC 1965 ATCAAATACAGCAAAA AGTAGTATAAATTTGTGCAAGGTCTGT GTCTTTTCCTTGGCCAGACTCCCTGAAAAAGAAG TATACTAC TTTTTGCTG 1966 CAGCAAAA A GTAGTATA 1967 Haemophilia ATTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCACA 1968 Ala200AspAATTTATACTACTTTTTG C TGTATTTGATGAAGGTTAGTGAGTC GCT-GATTTAATCTGAATTTTGGATTCCTGAAAGAAATCCTCGAGGATTTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACT 1969 AACCTTCATCAAATACA GCAAAAAGTAGTATAAATTTGTGCAA GGTCTGTGTCTTTTCCTTGGCCAGACTCCCTGAAA ACTTTTTG CTGTATTTG 1970 CAAATACA G CAAAAAGT 1971 Haemophilia ATTTTCAGGGAGTCTGGCCAAGGAAAAGACACAGACCTTGCAC 1972 Ala200ThrAAATTTATACTACTTTTT G CTGTATTTGATGAAGGTTAGTGAGT tGCT-ACTCTTAATCTGAATTTTGGATTCCTGAAAGAAATCCTAGGATTTCTTTCAGGAATCCAAAATTCAGATTAAGACTCACTA 31973 ACCTTCATCAAATACAG CAAAAAGTAGTATAAATTTGTGCAAG GTCTGTGTCTTTTCCTTGGCCAGACTCCCTGAAAA TACTTTTT GCTGTATTT 1974 AAATACAG C AAAAAGTA 1975 Haemophilia AAACTCCTTGATGCAGGATAGGGATGCTGCATCTGCTCGGGCC 1976 Val234PheTGGCCTAAAATGCACACA G TCAATGGTTATGTAAACAGGTCTC aGTC-TTCTGCCAGGTATGTACACACCTGCTCAACAATCCTCAGCTGAGGATTGTTGAGCAGGTGTGTACATACCTGGCAGAGACC 1977 TGTTTACATAACCATTGA CTGTGTGCATTTTAGGCCAGGCCCG AGCAGATGCAGCATCCCTATCCTGCATCAAGGAGTT TGCACACA GTCAATGGT 1978 ACCATTGA C TGTGTGCA 1979 Haemophilia AATTTCAGATTCTCTACTTCATAGCCATAGGTGTCTTATTCCTAC 1980 Gly247GluTTTACAGGTCTGATTG G ATGCCACAGGAAATCAGTCTATTGGC GGA-GAAATGTGATTGGAATGGGCACCACTCCTGAAGTGCATGCACTTCAGGAGTGGTGCCCATTCCAATCACATGCCAATAG 1981 ACTGATTTCCTGTGGCAT CCAATCAGACCTGTAAAGTAGGAAT AAGACACCTATGGCTATGAAGTAGAGAATCTGAAAT TCTGATTG GATGCCACA 1982 TGTGGCAT C CAATCAGA 1983 Haemophilia AATAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCAC 1984 Trp255CysAGGAAATCAGTCTATTG G CATGTGATTGGAATGGGCACCACT TGGc-TGTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT 1985 GCCCATTCCAATCACATG CCAATAGACTGATTTCCTGTGGCAT CCAATCAGACCTGTAAAGTAGGAATAAGACACCTAT GTCTATTG GCATGTGAT 1986 ATCACATG C CAATAGAC 1987 Haemophilia AATAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCAC 1988 Trp255TermAGGAAATCAGTCTATTG G CATGTGATTGGAATGGGCACCACT TGGc-TGACCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT 1989 GCCCATTCCAATCACATG CCAATAGACTGATTTCCTGTGGCAT CCAATCAGACCTGTAAAGTAGGAATAAGACACCTAT GTCTATTG GCATGTGAT 1990 ATCACATG C CAATAGAC 1991 Haemophilia AAGGTGTCTTATTCCTACTTTACAGGTCTGATTGGATGCCACAG 1992 His256LeuGAAATCAGTCTATTGGC A TGTGATTGGAATGGGCACCACTCC CAT-CTTTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTAATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTG 1993 GTGCCCATTCCAATCACA TGCCAATAGACTGATTTCCTGTGG CATCCAATCAGACCTGTAAAGTAGGAATAAGACACCT CTATTGGC ATGTGATTG 1994 CAATCACA T GCCAATAG 1995 Haemophilia ATATTCCTACTTTACAGGTCTGATTGGATGCCACAGGAAATCAG 1996 Gly259ArgTCTATTGGCATGTGATT G GAATGGGCACCACTCCTGAAGTGC tGGA-AGAACTCAATATTCCTCGAAGGTCACACATTTCTTGTGATCACAAGAAATGTGTGACCTTCGAGGAATATTGAGTGCACTTC 1997 AGGAGTGGTGCCCATTC CAATCACATGCCAATAGACTGATTT CCTGTGGCATCCAATCAGACCTGTAAAGTAGGAATA ATGTGATT GGAATGGGC 1998 GCCCATTC C AATCACAT 1999 Haemophilia ATTGGATGCCACAGGAAATCAGTCTATTGGCATGTGATTGGAAT 2000 Val266GlyGGGCACCACTCCTGAAG T GCACTCAATATTCCTCGAAGGTCA GTG-GGGCACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTAAGGACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGACCT 2001 TCGAGGAATATTGAGTGC ACTTCAGGAGTGGTGCCCATTCCA ATCACATGCCAATAGACTGATTTCCTGTGGCATCCAA TCCTGAAG TGCACTCAA 2002 TTGAGTGC A CTTCAGGA 2003 Haemophilia ACAGTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAAG 2004 Glu272GlyTGCACTCAATATTCCTCG A AGGTCACACATTTCTTGTGAGGAA GAA-GGACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAACGTTATTGGCGAGATTTCCAAGGACGCCTGGCGATGGTTCCTC 2005 ACAAGAAATGTGTGACCT TCGAGGAATATTGAGTGCACTTCAG GAGTGGTGCCCATTCCAATCACATGCCAATAGACTG ATTCCTCG AAGGTCACA 2006 TGTGACCT T CGAGGAAT 2007 Haemophilia ATCAGTCTATTGGCATGTGATTGGAATGGGCACCACTCCTGAA 2008 Glu272LysGTGCACTCAATATTCCTC G AAGGTCACACATTTCTTGTGAGGA I cGAA-AAAACCATCGCCAGGCGTCCTTGGAAATCTCGCCAATAATTATTGGCGAGATTCCAAGGACGCCTGGCGATGGTTCCTCA 2009 CAAGAAATGTGTGACCTT CGAGGAATATTGAGTGCACTTCAG GAGTGGTGCCCATTCCAATCACATGCCAATAGACTGA TATTCCTC GAAGGTCAC 2010 GTGACCTT C GAGGAATA 2011 Haemophilia AGGCATGTGATTGGAATGGGCACCACTCCTGAAGTGCACTCAA 2012 Thr275IleTATTCCTCGAAGGTCACA C ATTTCTTGTGAGGAACCATCGCCA ACA-ATAGGCGTCCTTGGAAATCTCGCCAATAACTTTCCTTACGTAAGGAAAGTTATTGGCGAGATTTCCAAGGACGCCTGGCGA 2013 TGGTTCCTCACAAGAAAT GTGTGACCTTCGAGGAATATTGAGT GCACTTCAGGAGTGGTGCCCATTCCAATCACATGCC AGGTCACA CATTTCTTG 2014 CAAGAAAT G TGTGACCT 2015 Haemophilia ATTGGAATGGGCACCACTCCTGAAGTGCACTCAATATTCCTCG 2016 Val278AlaAAGGTCACACATTTCTTG T GAGGAACCATCGCCAGGCGTCCT GTG-GCGTGGAAATCTCGCCAATAACTTTCCTTACTGCTCAAACGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCAAGGAC 2017 GCCTGGCGATGGTTCCTC ACAAGAAATGTGTGACCTTCGAGG AATATTGAGTGCACTTCAGGAGTGGTGCCCATTCCAA ATTTCTTG TGAGGAACC 2018 GGTTCCTC A CAAGAAAT 2019 Haemophilia ATGGGCACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTC 2020 Asn280IleACACATTTCTTGTGAGGA A CCATCGCCAGGCGTCCTTGGAAA AAC-ATCTCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGATTTCCA 2021 AGGACGCCTGGCGATGG TTCCTCACAAGAAATGTGTGACCTT CGAGGAATATTGAGTGCACTTCAGGAGTGGTGCCCA TGTGAGGA ACCATCGCC 2022 GGCGATGG T TCCTCACA 2023 Haemophilia AACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACAT 2024 Arg282CysTTCTTGTGAGGAACCAT C GCCAGGCGTCCTTGGAAATCTCGC tCGC-TGCCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGA 2025 TTTCCAAGGACGCCTGGC GATGGTTCCTCACAAGAAATGTGT GACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGGT GGAACCAT CGCCAGGCG 2026 CGCCTGGC G ATGGTTCC 2027 Haemophilia ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT 2028 Arg282HisTCTTGTGAGGAACCATC G CCAGGCGTCCTTGGAAATCTCGCC CGC-CACAATAACTTTCCTTACTGCTCAAACACTCTTGATGGATCCATCAAGAGTGTTTCAGCAGTAAGGAAAGTTATTGGCGAG 2029 ATTTCCAAGGACGCCTGG CGATGGTTCCTCACAAGAAATGTG TGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGG GAACCATC GCCAGGCGT 2030 ACGCCTGG C GATGGTTC 2031 Haemophilia ACCACTCCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATT 2032 Arg282LeuTCTTGTGAGGAACCATC G CCAGGCGTCCTTGGAAATCTCGCC CGC-CTCAATAACTTTCCTTACTGCTCAAACACTCTTGATGGATCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAG 2033 ATTTCCAAGGACGCCTGG CGATGGTTCCTCACAAGAAATGTG TGACCTTCGAGGAATATTGAGTGCACTTCAGGAGTGG GAACCATC GCCAGGCGT 2034 ACGCCTGG C GATGGTTC 2035 Haemophilia ACTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTGT 2036 Ala284GluGAGGAACCATCGCCAGG C GTCCTTGGAAATCTCGCCAATAAC GCG-GAGTTTCCTTACTGCTCAAACACTCTTGATGGACCTTGGCCAAGGTCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATT 2037 GGCGAGATTTCCAAGGAC GCCTGGCGATGGTTCCTCACAAG AAATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAG TCGCCAGG CGTCCTTGG 2038 CCAAGGAC G CCTGGCGA 2039 Haemophilia ACCTGAAGTGCACTCAATATTCCTCGAAGGTCACACATTTCTTG 2040 Ala284ProTGAGGAACCATCGCCAG G CGTCCTTGGAAATCTCGCCAATAA gGCG-CCGCTTTCCTTACTGCTCAAACACTCTTGATGGACTTTGCAAGGTCCATCAAGAGTGTTTGAGCAGTAAGGAAAGTTATTG 2041 GCGAGATTTCCAAGGACG CCTGGCGATGGTTCCTCACAAGAA ATGTGTGACCTTCGAGGAATATTGAGTGCACTTCAGG ATCGCCAG GCGTCCTTG 2042 CAAGGACG C CTGGCGAT 2043 Haemophilia ATATTCCTCGAAGGTCACACATTTCTTGTGAGGAACCATCGCCA 2044 Ser289LeuGGCGTCCTTGGAAATCT C GCCAATAACTTTCCTTACTGCTCAA TCG-TTGACACTCTTGATGGACCTTGGACAGTTTCTACTGTTAACAGTAGAAACTGTCCAAGGTCCATCAAGAGTGTTTGAGCA 2045 GTAAGGAAAGTTATTGGC GAGATTTCCAAGGACGCCTGGCGA TGGTTCCTCACAAGAAATGTGTGACCTTCGAGGAATA GGAAATCT CGCCAATAA 2046 TTATTGGC G AGATTTCC 2047 Haemophilia AGTCACACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGG 2048 Phe293SerAAATCTCGCCAATAACTT T CCTTACTGCTCAAACACTCTTGAT TTC-TCCGGACCTTGGACAGTTTCTACTGTTTTGTCATATCTCGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCATCAAG 2049 AGTGTTTGAGCAGTAAGG AAAGTTATTGGCGAGATTTCCAAG GACGCCTGGCGATGGTTCCTCACAAGAAATGTGTGAC AATAACTT TCCTTACTG 2050 CAGTAAGG A AAGTTATT 2051 Haemophilia AACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATC 2052 Thr295AlaTCGCCAATAACTTTCCTT A CTGCTCAAACACTCTTGATGGACC tACT-CCTTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCGGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGGTCCA 2053 TCAAGAGTGTTTGAGCAG TAAGGAAAGTTATTGGCGAGATTTC CAACGACGCCTCCCGATGGTTCCTCACAAGAAATGT CTTTCCTT ACTGCTCAA 2054 TTGAGCAG T AAGGAAAG 2055 Haemophilia ACATTTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCT 2056 Thr295IleCGCCAATAACTTTCCTTA C TGCTCAAACACTCTTCATGGACCT ACT-ATTTGGACAGTTTCTACTGTTTTGTCATATCTCTTCCCATGGGAAGAGATATGACAAAACAGTACAAACTGTCCAAGCTCC 2057 ATCAAGAGTGTTTGAGCA GTAAGGAAAGTTATTGGCGAGATTT CCAAGGACGCCTCGCGATGGTTCCTCACAAGAAATG TTTCCTTA CTGCTCAAA 2058 TTTGAGCA G TAACGAAA 2059 Haemophilia ATTCTTGTGAGGAACCATCGCCAGGCGTCCTTGGAAATCTCGC 2060 Ala296ValCAATAACTTTCCTTACTG C TCAAACACTCTTGATGGACCTTGG CCT-GTTACAGTTTCTACTGTTTTGTCATATCTCTTCCCACCATGGTGGGAAGAGATATGACAAAACAGTAGAAACTGTCCAAGG 2061 TCCATCAAGAGTGTTTGA GCAGTAAGGAAAGTTATTCGCGAG ATTTCCAAGGACGCCTGGCGATCGTTGGTCACAAGAA CCTTACTG CTCAAACAC 2062 GTGTTTGA G CAGTAAGC 2063 Haemophilia ATCTCGCCAATAACTTTCCTTACTGCTCAAACACTCTTCATGGA 2064 Leu308ProCCTTGGACAGTTTCTAC T GTTTTGTCATATCTCTTCCCACCAA CTG-CCGCATGGTAATATCTTGGATCTTTAAAATGAATATTATAATATTCATTTTAAAGATCCAAGATATTACCATGTTGGTGGGA 2065 AGAGATATGACAAAAC AGTAGAAACTGTCCAAGGTCCATCAA GAGTGTTTGAGCAGTAAGGAAAGTTATTGGCGAGA GTTTCTAC TGTTTTGTC 2066 GACAAAAC A GTAGAAAC 2067 Haemophilia AACAGCCTAATATAGCAAGACACTCTGACATTGTTTGGTTTGTC 2068 Glu321LysTGACTCCAGATGGCATG G AAGCTTATGTCAAAGTAGACAGCT gGAA-AAAGTCCAGAGGAACCCCAACTACGAATGAAAAATAATGCATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGACAGCTGTC 2069 TACTTTGACATAAGCTT CCATGCCATCTGGAGTCAGACAAACC AAACAATGTCAGAGTGTCTTGCTATATTAGGCTGT ATGGCATG GAAGCTTAT 2070 ATAAGCTT C CATGCCAT 2071 Haemophilia AATATAGCAAGACACTCTGACATTGTTTGGTTTGTCTGACTCCA 2072 Tyr323TermGATGGCATGGAAGCTTA T GTCAAAGTAGACAGCTGTCCAGAG TATg-TAAGAACCCCAACTACGAATGAAAAATAATGAAGAAGCGCGCTTCTTCATTATTTTTCATTCGTAGTTGGGGTTCCTCTGGA 2073 CAGCTGTCTACTTTGAC ATAAGCTTCCATGCCATCTGGAGTCA GACAAACCAAACAATGTCAGAGTGTCTTGCTATAT GAAGCTTA TGTCAAAGT 2074 ACTTTGAC A TAAGCTTC 2075 Haemophilia AAAGACACTCTGACATTGTTTGGTTTGTCTGACTCCAGATGGCA 2076 Val326LeuTGGAAGCTTATGTCAAA G TAGACAGCTGTCCAGAGGAACCCC aGTA-CTAAACTACGAATGAAAAATAATGAAGAAGCGGAAGACTAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAGTTGGGGTTC 2077 CTCTGGACAGCTGTCTA CTTTGACATAAGCTTCCATGCCATCT GGAGTCAGACAAACCAAACAATGTCAGAGTGTCTT ATGTCAAA GTAGACAGC 2078 GCTGTCTA C TTTGACAT 2079 Haemophilia ATGACATTGTTTGGTTTGTCTGACTCCAGATGGCATGGAAGCTT 2080 Cys329ArgATGTCAAAGTAGACAGC T GTCCAGAGGAACCCCAACTACGAA cTGT-CGTTGAAAAATAATGAAGAAGCGGAAGACTATGATGATGCATCATCATAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAGT 2081 TGGGGTTCCTCTGGAC AGCTGTCTACTTTGACATAAGCTTCC ATGCCATCTGGAGTCAGACAAACCAAACAATGTCA TAGACAGC TGTCCAGAG 2082 CTCTGGAC A GCTGTCTA 2083 Haemophilia AGACATTGTTTGGTTTGTCTGACTCCAGATGGCATGGAAGCTTA 2084 Cys329TyrTGTCAAAGTAGACAGCT G TCCAGAGGAACCCCAACTACGAAT TGT-TATGAAAAATAATGAAGAAGCGGAAGACTATGATGATGATCATCATCATAGTCTTCCGCTTCTTCATTATTTTTCATTCGTAG 2085 TTGGGGTTCCTCTGGA CAGCTGTCTACTTTGACATAAGCTTCC ATGCCATCTGGAGTCAGACAAACCAAACAATGTC AGACAGCT GTCCAGAGG 2086 CCTCTGGA C AGCTGTCT 2087 Haemophilia AACTCCAGATGGCATGGAAGCTTATGTCAAAGTAGACAGCTGT 2088 Arg336TermCCAGAGGAACCCCAACTA C GAATGAAAAATAATGAAGAAGCG aCGA-TGAGAAGACTATGATGATGATCTTACTGATTCTGAAATGGCCATTTCAGAATCAGTAAGATCATCATCATAGTCTTCCGCTTC 2089 TTCATTATTTTTCATTC GTAGTTGGGGTTCCTCTGGACAGCTG TCTACTTTGACATAAGCTTCCATGCCATCTGGAGT CCCAACTA CGAATGAAA 2090 TTTCATTC G TAGTTGGG 2091 Haemophilia AGATTCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTC 2092 Arg372CysCTTCCTTTATCCAAATT C GCTCAGTTGCCAAGAAGCATCCTAA tCGC-TGCAACTTGGGTACATTACATTGCTGCTGAAGAGGAGGCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGATG 2093 CTTCTTGGCAACTGAGC GAATTTGGATAAAGGAAGGAGAGTT GTCATCATCAAACCTGACCACATCCATTTCAGAATC TCCAAATT CGCTCAGTT 2094 AACTGAGC G AATTTGGA 2095 Haemophilia AATTCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCC 2096 Arg372HisTTCCTTTATCCAAATTC G CTCAGTTGCCAAGAAGCATCCTAAA CGC-CACACTTGGGTACATTACATTGCTGCTGAAGAGGAGGATCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGGAT 2097 GCTTCTTGGCAACTGAG CGAATTTGGATAAAGGAAGGAGAGT TGTCATCATCAAACCTGACCACATCCATTTCAGAAT CCAAATTC GCTCAGTTG 2098 CAACTGAG C GAATTTGG 2099 Haemophilia ACTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTTC 2100 Ser373LeuCTTTATCCAAATTCGCT C AGTTGCCAAGAAGCATCCTAAAACT TCA-TTATGGGTACATTACATTGCTGCTGAAGAGGAGGACTGCAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAG 2101 GATGCTTCTTGGCAACT GAGCGAATTTGGATAAAGGAAGGAG AGTTGTCATCATCAAACCTGACCACATCCATTTCAG AATTCGCT CAGTTGCCA 2102 TGGCAACT G AGCGAATT 2103 Haemophilia ATCTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTT 2104 Ser373ProCCTTTATCCAAATTCGC T CAGTTGCCAAGAAGCATCCTAAAAC cTCA-CCATTGGGTACATTACATTGCTGCTGAAGAGGAGGACTAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAGG 2105 ATGCTTCTTGGCAACTG AGCGAATTTGGATAAAGGAAGGAGA GTTGTCATCATCAAACCTGACCACATCCATTTCAGA AAATTCGC TCAGTTGCC 2106 GGCAACTG A GCGAATTT 2107 Haemophilia ACTGAAATGGATGTGGTCAGGTTTGATGATGACAACTCTCCTTC 2108 Ser373TermCTTTATCCAAATTCGCT C AGTTGCCAAGAAGCATCCTAAAACT I TCA-TAATGGGTACATTACATTGCTGCTGAAGAGGAGGACTGCAGTCCTCCTCTTCAGCAGCAATGTAATGTACCCAAGTTTTAG 2109 GATGCTTCTTGGCAACT GAGCGAATTTGGATAAAGGAAGGAG AGTTGTCATCATCAAACCTGACCACATCCATTTCAG AATTCGCT CAGTTGCCA 2110 TGGCAACT G AGCGAATT 2111 Haemophilia ACCTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTA 2112 Ile386PheAAACTTGGGTACATTAC A TTGCTGCTGAAGAGGAGGACTGGG cATT-TTTACTATGCTCCCTTAGTCCTCGCCCCCGATGACAGGTACCTGTCATCGGGGGCGAGGACTAAGGGAGCATAGTCCCAG 2113 TCCTCCTCTTCAGCAGCAA TGTAATGTACCCAAGTTTTAGGAT GCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAGG TACATTAC ATTGCTGCT 2114 AGCAGCAA T GTAATGTA 2115 Haemophilia ACTTCCTTTATCCAAATTCGCTCAGTTGCCAAGAAGCATCCTAA 2116 Ile386SerAACTTGGGTACATTACA T TGCTGCTGAAGAGGAGGACTGGGA ATT-AGTCTATGCTCCCTTAGTCCTCGCCCCCGATGACAGGTATACCTGTCATCGGGGGCGAGGACTAAGGGAGCATAGTCCCA 2117 GTCCTCCTCTTCAGCAGCA ATGTAATGTACCCAAGTTTTAGGA TGCTTCTTGGCAACTGAGCGAATTTGGATAAAGGAAG ACATTACA TTGCTGCTG 2118 CAGCAGCA A TGTAATGT 2119 Haemophilia AAAATTCGCTCAGTTGCCAAGAAGCATCCTAAAACTTGGGTACA 2120 Glu390GlyTTACATTGCTGCTGAAG A GGAGGACTGGGACTATGCTCCCTT GAG-GGGAGTCCTCGCCCCCGATGACAGGTAAGCACTTTTTGATCAAAAAGTGCTTACCTGTCATCGGGGGCGAGGACTAAGGGA 2121 GCATAGTCCCAGTCCTCC TCTTCAGCAGCAATGTAATGTACC CAAGTTTTAGGATGCTTCTTGGCAACTGAGCGAATTT TGCTGAAG AGGAGGACT 2122 AGTCCTCC T CTTCAGCA 2123 Haemophilia ATCAGTTGCCAAGAAGCATCCTAAAACTTGGGTACATTACATTG 2124 Trp393GlyCTGCTGAAGAGGAGGAC T GGGACTATGCTCCCTTAGTCCTCG cTGG-GGGCCCCCGATGACAGGTAAGCACTTTTTGACTATTGGTACCAATAGTCAAAAAGTGCTTACCTGTCATCGGGGGCGAGGA 2125 CTAAGGGAGCATAGTCCC AGTCCTCCTCTTCAGCAGCAATGT AATGTACCCAAGTTTTAGGATGCTTCTTGGCAACTGA AGGAGGAC TGGGACTAT 2126 ATAGTCCC A GTCCTCCT 2127 Haemophilia AGCCTACCTAGAATTTTTCTTCCCAACCTCTCATCTTTTTTTCTC 2128 Lys408IleTTATACAGAAGTTATAAAAGTCAATATTTGAACAATGGCCCTC AAA-ATAAGCGGATTGGTAGGAAGTACAAAAAAGTCCGATTAATCGGACTTTTTTGTACTTCCTACCAATCCGCTGAGGGCCAT 2129 TGTTCAAATATTGACTT TTATAACTTCTGTATAAGAGAAAAAAA GATGAGAGGTTGGGAAGAAAAATTCTAGGTAGGC AAGTTATA AAAGTCAAT 2130 ATTGACTT T TATAACTT 2131 Haemophilia ATTTTCTTCCCAACCTCTCATCTTTTTTTCTCTTATACAGAAGTT 2132 Leu412PheATAAAAGTCAATATTT G AACAATGGCCCTCAGCGGATTGGTAG TTGa-TTTGAAGTACAAAAAAGTCCGATTTATGGCATACACATGTGTATGCCATAAATCGGACTTTTTTGTACTTCCTACCAATC 2133 CGCTGAGGGCCATTGTT CAAATATTGACTTTTATAACTTCTGT ATAAGAGAAAAAAAGATGAGAGGTTGGGAAGAAAA CAATATTT GAACAATGG 2134 CCATTGTT C AAATATTG 2135 Haemophilia ATCATCTTTTTTTCTCTTATACAGAAGTTATAAAAGTCAATATTTG 2136 Arg418TrpAACAATGGCCCTCAG C GGATTGGTAGGAAGTACAAAAAAGTC gCGG-TGGCGATTTATGGCATACACAGATGAAACCTTTAAGATCTTAAAGGTTTCATCTGTGTATGCCATAAATCGGACTTTTTTG 2137 TACTTCCTACCAATCC GCTGAGGGCCATTGTTCAAATATTGAC TTTTATAACTTCTGTATAAGAGAAAAAAAGATGA GCCCTCAG CGGATTGGT 2138 ACCAATCC G CTGAGGGC 2139 Haemophilia ATTTTTCTCTTATACAGAAGTTATAAAAGTCAATATTTGAACAAT 2140 Gly420ValGGCCCTCAGCGGATTG G TAGGAAGTACAAAAAAGTCCGATTT GGT-GTrATGGCATACACAGATGAAACCTTTAAGACTCGTGATCACGAGTCTTAAAGGTTTCATCTGTGTATGCCATAAATCGGA 2141 CTTTTTTGTACTTCCTA CCAATCCGCTGAGGGCCATTGTTCAA ATATTGACTTTTATAACTTCTGTATAAGAGAAAAA GCGGATTG GTAGGAAGT 2142 ACTTCCTA C CAATCCGC 2143 Haemophilia AGAAGTTATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGAT 2144 Lys425ArgTGGTAGGAAGTACAAAA A AGTCCGATTTATGGCATACACAGAT AAA-AGAGAAACCTTTAAGACTCGTGAAGCTATTCAGCATGATCATGCTGAATAGCTTCACGAGTCTTAAAGGTTTCATCTGTGT 2145 ATGCCATAAATCGGACT TTTTTGTACTTCCTACCAATCCGCTG AGGGCCATTGTTCAAATATTGACTTTTATAACTTC GTACAAAA AAGTCCGAT 2146 ATCGGACT T TTTTGTAC 2147 Haemophilia ATATAAAAGTCAATATTTGAACAATGGCCCTCAGCGGATTGGTA 2148 Arg427TermGGAAGTACAAAAAAGTC C GATTTATGGCATACACAGATGAAAC cCGA-TGACTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGCTGATTCATGCTGAATAGCTTCACGAGTCTTAAAGGTTTCATC 2149 TGTGTATGCCATAAATC GGACTTTTTTGTACTTCCTACCAATC CGCTGAGGGCCATTGTTCAAATATTGACTTTTATA AAAAAGTC CGATTTATG 2150 CATAAATC G GACTTTTT 2151 Haemophilia ATATTTGAACAATGGCCCTCAGCGGATTGGTAGGAAGTACAAA 2152 Tyr431AsnAAAGTCCGATTTATGGCA T ACACAGATGAAACCTTTAAGACTC aTAC-AACGTGAAGCTATTCAGCATGAATCAGGAATCTTGGGACGTCCCAAGATTCCTGATTCATGCTGAATAGCTTCACGAGTCTT 2153 AAAGGTTTCATCTGTGT ATGCCATAAATCGGACTTTTTTGTAC TTCCTACCAATCCGCTGAGGGCCATTGTTCAAATA TTATGGCA TACACAGAT 2154 ATCTGTGT A TGCCATAA 2155 Haemophilia AGCCCTCAGCGGATTGGTAGGAAGTACAAAAAAGTCCGATTTA 2156 Thr435IleTGGCATACACAGATGAAA C CTTTAAGACTCGTGAAGCTATTCA ACC-ATCGCATGAATCAGGAATCTTGGGACCTTTACTTTATGGCCATAAAGTAAAGGTCCCAAGATTCCTGATTCATGCTGAATAG 2157 CTTCACGAGTCTTAAAG GTTTCATCTGTGTATGCCATAAATCG GACTTTTTTGTACTTCCTACCAATCCGCTGAGGGC AGATGAAA CCTTTAAGA 2158 TCTTAAAG G TTTCATCT 2159 Haemophilia AACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCAGCATGA 2160 Pro451LeuATCAGGAATCTTGGGAC C TTTACTTTATGGGGAAGTTGGAGA CCT-CTTCACACTGTTGGTAAGTTGAAGAAAAGATTTAAGGTCGACCTTAAATCTTTTCTTCAACTTACCAACAGTGTGTCTCCAA 2161 CTTCCCCATAAAGTAAA GGTCCCAAGATTCGTGATTCATGCTG AATAGCTTCACGAGTCTTAAAGGTTTCATCTGTGT CTTGGGAC CTTTACTTT 2162 AAAGTAAA G GTCCCAAG 2163 Haemophilia ATACACAGATGAAACCTTTAAGACTCGTGAAGCTATTCAGCATG 2164 Pro451ThrAATCAGGAATCTTGGGA C CTTTACTTTATGGGGAAGTTGGAGA aCCT-ACTCACACTGTTGGTAAGTTGAAGAAAAGATTTAAGGTACCTTAAATCTTTTCTTCAACTTACCAACAGTGTGTCTCCAACT 2165 TCCCCATAAAGTAAAG GTCCCAAGATTCCTGATTCATGCTGAA TAGCTTCACGAGTCTTAAAGGTTTCATCTGTGTA TCTTGGGA CCTTTACTT 2166 AAGTAAAG G TCCCAAGA 2167 Haemophilia AACCTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGGAATCT 2168 Gly455ArgTGGGACCTTTACTTTAT G GGGAAGTTGGAGACACACTGTTGG tGGG-AGGTAAGTTGAAGAAAAGATTTAAGGTCAGGTAAGAAGATCTTCTTACCTGACCTTAAATCTTTTCTTCAACTTACCAACAGT 2169 GTGTCTCCAACTTCCC CATAAAGTAAAGGTCCCAAGATTCCTG ATTCATGCTGAATAGCTTCACGAGTCTTAAAGGT TACTTTAT GGGGAAGTT 2170 AACTTCCC C ATAAAGTA 2171 Haemophilia ACCTTTAAGACTCGTGAAGCTATTCAGCATGAATCAGGAATCTT 2172 Gly455GluGGGACCTTTACTTTATG G GGAAGTTGGAGACACACTGTTGGT GGG-GAGAAGTTGAAGAAAAGATTTAAGGTCAGGTAAGAAGAATTCTTCTTACCTGACCTTAAATCTTTTCTTCAACTTACCAACAG 2173 TGTGTCTCCAACTTCC CCATAAAGTAAAGGTCCCAAGATTCCT GATTCATGCTGAATAGCTTCACGAGTCTTAAAGG ACTTTATG GGGAAGTTG 2174 CAACTTCC C CATAAAGT 2175 Haemophilia ACGTGAAGCTATTCAGCATGAATCAGGAATCTTGGGACCTTTAC 2176 Asp459AsnTTTATGGGGAAGTTGGA G ACACACTGTTGGTAAGTTGAAGAA aGAC-AACAAGATTTAAGGTCAGGTAAGAAGAAAAAGTCTGGAGCTCCAGACTTTTTCTTCTTACCTGACCTTAAATCTTTTCTTCAA 2177 CTTACCAACAGTGTGT CTCCAACTTCCCCATAAAGTAAAGGTC CCAAGATTCCTGATTCATGCTGAATAGCTTCACG AAGTTGGA GACACACTG 2178 CAGTGTGT C TCCAACTT 2179 Haemophilia ATGTTGATCCTAGTCGTTTTAGGATTTGATCTTAGATCTCGCTTA 2180 Phe465CysTACTTTCAGATTATAT T TAAGAATCAAGCAAGCAGACCATATAA TTT-TGTCATCTACCCTCACGGAATCACTGATGTCCGTCCGGACGGACATCAGTGATTCCGTGAGGGTAGATGTTATATGGT 2181 CTGCTTGCTTGATTCTTA AATATAATCTGAAAGTATAAGCGAG ATCTAAGATCAAATCCTAAAACGACTAGGATCAACA GATTATAT TTAAGAATC 2182 GATTCTTA A ATATAATC 2183 Haemophilia ATCGTTTTAGGATTTGATCTTAGATCTCGCTTATACTTTCAGATT 2184 Ala469GlyATATTTAAGAATCAAG C AAGCAGACCATATAACATCTACCCTC GCA-GGAACGGAATCACTGATGTCCGTCCTTTGTATTCAAGCTTGAATACAAAGGACGGACATCAGTGATTCCGTGAGGGTAG 2185 ATGTTATATGGTCTGCTT GCTTGATTCTTAAATATAATCTGAAA GTATAAGCGAGATCTAAGATCAAATCCTAAAACGA GAATCAAG CAAGCAGAC 2186 GTCTGCTT G CTTGATTC 2187 Haemophilia ATTAGGATTTGATCTTAGATCTCGCTTATACTTTCAGATTATATT 2188 Arg471GlyTAAGAATCAAGCAAGC A GACCATATAACATCTACCCTCACGG cAGA-GGAAATCACTGATGTCCGTCCTTTGTATTCAAGGAGATATCTCCTTGAATACAAAGGACGGACATCAGTGATTCCGTGAG 2189 GGTAGATGTTATATGGTC TGCTTGCTTGATTCTTAAATATAATC TGAAAGTATAAGCGAGATCTAAGATCAAATCCTAA AAGCAAGC AGACCATAT 2190 ATATGGTC T GCTTGCTT 2191 Haemophilia ATTGATCTTAGATCTCGCTTATACTTTCAGATTATATTTAAGAAT 2192 Tyr473CysCAAGCAAGCAGACCAT A TAACATCTACCCTCACGGAATCACT TAT-TGTGATGTCCGTCCTTTGTATTCAAGGAGATTACCAAATTTGGTAATCTCCTTGAATACAAAGGACGGACATCAGTGATTC 2193 CGTGAGGGTAGATGTTA TATGGTCTGCTTGCTTGATTCTTAAA TATAATCTGAAAGTATAAGCGAGATCTAAGATCAA CAGACCAT ATAACATCT 2194 AGATGTTA T ATGGTCTG 2195 Haemophilia ATTTGATCTTAGATCTCGCTTATACTTTCAGATTATATTTAAGAA 2196 Tyr473HisTCAAGCAAGCAGACCA T ATAACATCTACCCTCACGGAATCACT aTAT-CATGATGTCCGTCCTTTGTATTCAAGGAGATTACCAATTGGTAATCTCCTTGAATACAAAGGACGGACATCAGTGATTCC 2197 GTGAGGGTAGATGTTAT ATGGTCTGCTTGCTTGATTCTTAAAT ATAATCTGAAAGTATAAGCGAGATCTAAGATCAAA GCAGACCA TATAACATC 2198 GATGTTAT A TGGTCTGC 2199 Haemophilia ATTAGATCTCGCTTATACTTTCAGATTATATTTAAGAATCAAGCA 2200 Ile475ThrAGCAGACCATATAACA T CTACCCTCACGGAATCACTGATGTCC ATC-ACCGTCCTTTGTATTCAAGGAGATTACCAAAAGGTAATTACCTTTTGGTAATCTCCTTGAATACAAAGGACGGACATCAG 2201 TGATTCCGTGAGGGTAG ATGTTATATGGTCTGCTTGCTTGATT CTTAAATATAATCTGAAAGTATAAGCGAGATCTAA ATATAACA TCTACCCTC 2202 GAGGGTAG A TGTTATAT 2203 Haemophilia ATTATACTTTCAGATTATATTTAAGAATCAAGCAAGCAGACCATA 2204 Gly479ArgTAACATCTACCCTCAC G GAATCACTGATGTCCGTCCTTTGTAT cGGA-AGATCAAGGAGATTACCAAAAGGTAAATATTCCCTCGCGAGGGAATATTTACCTTTTGGTAATCTCCTTGAATACAAAGG 2205ACGGACATCAGTGATTCCGTGAGGGTAGATGTTATATGGTCTGCTTGCTTGATTCTTAAATATAATCTGAAAGTATAA ACCCTCAC G GAATCACT 2206 AGTGATTC CGTGAGGGT 2207 Haemophilia A CCAATTCTGCCAGGAGAAATATTCAAATATAAATGGACAGTGA2208 Thr522Ser CTGTAGAAGATGGGCCA A CTAAATCAGATCCTCGGTGCCTGA aACT-TCTCCCGCTATTACTCTAGTTTCGTTAATATGGAGAGAGCTCTCTCCATATTAACGAAACTAGAGTAATAGCGGGTCAGGC 2209 ACCGAGGATCTGATTTAG TTGGCCCATCTTCTACAGTCACTGT CCATTTATATTTGAATATTTCTCCTGGCAGAATTGG ATGGGCCA ACTAAATCA 2210 TGATTTAG T TGGCCCAT 221T Haemophilia ACCAGGAGAAATATTCAAATATAAATGGACAGTGACTGTAGAAG 2212 Asp525AsnATGGGCCAACTAAATCA G ATCCTCGGTGCCTGACCCGCTATT aGAT-AATACTCTAGTTTCGTTAATATGGAGAGAGATCTAGCTTAAGCTAGATCTCTCTCCATATTAACGAAACTAGAGTAATAGCG 2213 GGTCAGGCACCGAGGAT CTGATTTAGTTGGCCCATCTTCTAC AGTCACTGTCCATTTATATTTGAATATTTCTCCTGG CTAAATCA GATCCTCGG 2214 CCGAGGAT C TGATTTAG 2215 Haemophilia AGAAATATTCAAATATAAATGGACAGTGACTGTAGAAGATGGGC 2216 Arg527TrpCAACTAAATCAGATCCT C GGTGCCTGACCCGCTATTACTCTA tCGG-TGGGTTTCGTTAATATGGAGAGAGATCTAGCTTCAGGACGTCCTGAAGCTAGATCTCTCTCCATATTAACGAAACTAGAGTA 2217 ATAGCGGGTCAGGCACC GAGGATCTGATTTAGTTGGCCCATC TTCTACAGTCACTGTCCATTTATATTTGAATATTTC CAGATCCT CGGTGCCTG 2218 CAGGCACC G AGGATCTG 2219 Haemophilia ATATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCA 2220 Arg531CysGATCCTCGGTGCCTGACC C GCTATTACTCTAGTTTCGTTAATA cCGC-TGCTGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA 2221 CGAAACTAGAGTAATAGC GGGTCAGGCACCGAGGATCTGATT TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTATA GCCTGACC CGCTATTAC 2222 GTAATAGC G GGTCAGGC 2223 Haemophilia ATATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCA 2224 Arg531GlyGATCCTCGGTGCCTGACC C GCTATTACTCTAGTTTCGTTAATA cCGC-GGCTGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA 2225 CGAAACTAGAGTAATAGC GGGTCAGGCACCGAGGATCTGATT TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTATA GCCTGACC CGCTATTAC 2226 GTAATAGC G GGTCAGGC 2227 Haemophilia AATAAATGGACAGTGACTGTAGAAGATGGGCCAACTAAATCAG 2228 Arg531HisATCCTCGGTGCCTGACCC G CTATTACTCTAGTTTCGTTAATAT I CGC-CACGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTAGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAA 2229 CGAAACTAGAGTAATAG CGGGTCAGGCACCGAGGATCTGATT TAGTTGGCCCATCTTCTACAGTCACTGTCCATTTAT CCTGACCC GCTATTACT 2230 AGTAATAG C GGGTCAGG 2231 Haemophilia AACAGTGACTGTAGAAGATGGGCCAACTAAATCAGATCCTCGG 2232 Ser534ProTGCCTGACCCGCTATTAC T CTAGTTTCGTTAATATGGAGAGAG cTCT-CCTATCTAGCTTCAGGACTCATTGGCCCTCTCCTCATCTAGATGAGGAGAGGGCCAATGAGTCCTGAAGCTAGATCTCTCT 2233 CCATATTAACGAAACTAG AGTAATAGCGGGTCAGGCACCGAG GATCTGATTTAGTTGGCCCATCTTCTACAGTCACTGT GCTATTAC TCTAGTTTC 2234 GAAACTAG A GTAATAGC 2235 Haemophilia AGTGACTGTAGAAGATGGGCCAACTAAATCAGATCCTCGGTGC 2236 Ser535GlyCTGACCCGCTATTACTCT A GTTTCGTTAATATGGAGAGAGATC tAGT-GGTTAGCTTCAGGACTCATTGGCCCTCTCCTCATCTGCTAGCAGATGAGGAGAGGGCCAATGAGTCCTGAAGCTAGATCTC 2237 TCTCCATATTAACGAAAC TAGAGTAATAGCGGGTCAGGCACC GAGGATCTGATTTAGTTGGCCCATCTTCTACAGTCAC ATTACTCT AGTTTCGTT 2238 AACGAAAC T AGAGTAAT 2239 Haemophilia ATAGAAGATGGGCCAACTAAATCAGATCCTCGGTGCCTGACCC 2240 Val537AspGCTATTACTCTAGTTTCG T TAATATGGAGAGAGATCTAGCTTC GTT-GATAGGACTCATTGGCCCTCTCCTCATCTGCTACAAAGATCTTTGTAGCAGATGAGGAGAGGGCCAATGAGTCCTGAAGCT 2241 AGATCTCTCTCCATATTA ACGAAACTAGAGTAATAGCGGGTCA GGCACCGAGGATCTGATTTAGTTGGCCCATCTTCTA TAGTTTCG TTAATATGG 2242 CCATATTA A CGAAACTA 2243 Haemophilia ACAACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTA 2244 Arg541ThrGTTTCGTTAATATGGAGA G AGATCTAGCTTCAGGACTCATTGG AGA-ACACCCTCTCCTCATCTGCTACAAAGAATCTGTAGATCATGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAATG 2245 AGTCCTGAAGCTAGATCT CTCTCCATATTAACGAAACTAGAGT AATAGCGGGTCAGGCACCGAGGATCTGATTTAGTTG TATGGAGA GAGATCTAG 2246 CTAGATCT C TCTCCATA 2247 Haemophilia ACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTTT 2248 Asp542GlyCGTTAATATGGAGAGAG A TCTAGCTTCAGGACTCATTGGCCC I GAT-GGTTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAAGCTTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCA 2249 ATGAGTCCTGAAGCTAGA TCTCTCTCCATATTAACGAAACTAG AGTAATAGCGGGTCAGGCACCGAGGATCTGATTTAG GGAGAGAG ATCTAGCTT 2250 AAGCTAGA T CTCTCTCC 2251 Haemophilia AACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTT 2252 Asp542HisTCGTTAATATGGAGAGA G ATCTAGCTTCAGGACTCATTGGCC aGAT-CATCTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAATTTGATCTACAGATTCTTTGTAGCAGATGAGGAGAGGGCCAAT 2253 GAGTCCTGAAGCTAGAT CTCTCTCCATATTAACGAAACTAGAG TAATAGCGGGTCAGGCACCGAGGATCTGATTTAGT TGGAGAGA GATCTAGCT 2254 AGCTAGAT C TCTCTCCA 2255 Haemophilia AACTAAATCAGATCCTCGGTGCCTGACCCGCTATTACTCTAGTT 2256 Asp542TyrTCGTTAATATGGAGAGA G ATCTAGCTTCAGGACTCATTGGCC aGAT-TATCTCTCCTCATCTGCTACAAAGAATCTGTAGATCAAATTTGATCTACAGATTGTTTGTAGCAGATGAGGAGAGGGCCAAT 2257 GAGTCCTGAAGCTAGAT CTCTCTCCATATTAACGAAACTAGAG TAATAGCGGGTCAGGCACCGAGGATCTGATTTAGT TGGAGAGA GATCTAGCT 2258 AGCTAGAT C TCTCTCCA 2259 Haemophilia AGTTAATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCT 2260 Glu557TermCTCCTCATCTGCTACAAA G AATCTGTAGATCAAAGAGGAAACC aGAA-TAAAGGTGAGTTCTTGCCTTTCCAAGTGCTGGGTTTCATATGAAACCCAGCACTTGGAAAGGCAAGAACTCACCTGGTTTC 2261 CTCTTTGATCTACAGATT CTTTGTAGCAGATGAGGAGAGGGC CAATGAGTCCTGAAGCTAGATCTCTCTCCATATTAAC GCTACAAA GAATGTGTA 2262 TACAGATT C TTTGTAGC 2263 Haemophilia AATATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTCC 2264 Ser558PheTCATCTGCTACAAAGAAT C TGTAGATCAAAGAGGAAACCAGGT TCT-TTTGAGTTCTTGCCTTTCCAAGTGCTGGGTTTCATTCTCGAGAATGAAACCCAGCACTTGGAAAGGCAAGAACTCACCTGG 2265 TTTCCTCTTTGATCTACA GATTCTTTGTAGCAGATGAGGAGAG GGCCAATGAGTCCTGAAGCTAGATCTCTCTCCATAT CAAAGAAT CTGTAGATC 2266 GATCTACA G ATTCTTTG 2267 Haemophilia ATGGAGAGAGATCTAGCTTCAGGACTCATTGGCCCTCTCCTCA 2268 Val559AlaTCTGCTACAAAGAATCTG T AGATCAAAGAGGAAACCAGGTGA GTA-GCAGTTCTTGCCTTTCCAAGTGCTGGGTTTCATTCTCAGTACTGAGAATGAAACCCAGCACTTGGAAAGGCAAGAACTCACC 2269 TGGTTTCCTCTTTGATCT ACAGATTCTTTGTAGCAGATGAGGA GAGGGCCAATGAGTCCTGAAGCTAGATCTCTCTCCA AGAATCTG TAGATCAAA 2270 TTTGATCT A CAGATTCT 2271

EXAMPLE 14 Hemophilia—Factor IX Deficiency

[0135] The attached table discloses the correcting oligonucleotide basesequences for the Factor IX oligonucleotides of the invention. TABLE 21Factor IX Mutations and Genome-Correcting Oligos Clinical Phenotype &SEQ ID Mutation Correcting Oligos NO: Haemophilia BATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAA 2272 Asn2AspTCGGCCAAAGAGGTAT A ATTCAGGTAAATTGGAAGAGTTTGTT tAAT-GATCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAATTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT 2273 TCCAATTTACCTGAAT TATACCTCTTTGGCCGATTCAGAATTTT GTTGGCGTTTTCATGATCAAGAAAAACTGAAAT AGAGGTAT AATTCAGGT 2274 ACCTGAAT TATACCTCT 2275 Haemophilia BTTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAAT 2276 Asn2IleCGGCCAAAGAGGTATA A TTCAGGTAAATTGGAAGAGTTTGTT AAT-ATTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAATTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTC 2277 TTCCAATTTACCTGAA TTATACCTCTTTGGCCGATTCAGAATTT TGTTGGCGTTTTCATGATCAAGAAAAACTGAAA GAGGTATA ATTCAGGTA 2278 TACCTGAA T TATACCTC 2279 Haemophilia BATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAA 2280 Asn2TyrTCGGCCAAAGAGGTAT A ATTCAGGTAAATTGGAAGAGTTTGTT tAAT-TATCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAATTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAATCTCT 2281 TCCAATTTACCTGAAT TATACCTCTTTGGCCGATTCAGAATTTT GTTGGCGTTTTCATGATCAAGAAAAACTGAAAT AGAGGTAT AATTCAGGT 2282 ACCTGAAT T ATACCTCT 2283 Haemophilia BTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATC 2284 Ser3ProGGCCAAAGAGGTATAAT T CAGGTAAATTGGAAGAGTTTGTTCA tTCA-CCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAAC 2285 TCTTCCAATTTACCTG AATTATACCTCTTTGGCCGATTCAGAA TTTTGTTGGCGTTTTCATGATCAAGAAAAACTGA GGTATAAT TCAGGTAAA 2286 TTTACCTG A ATTATACC 2287 Haemophilia BTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCC 2288 Gly4AspAAAGAGGTATAATTCAG G TAAATTGGAAGAGTTTGTTCAAGGG GGT-GATAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGCTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC 2289 AAACTCTTCCAATTTA CCTGAATTATACCTCTTTGGCCGATTCA GAATTTTGTTGGCGTTTTCATGATCAAGAAAAA TAATTCAG GTAAATTGG 2290 CCAATTTA C CTGAATTA 2291 Haemophilia BGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGC 2292 Gly4SerCAAAGAGGTATAATTCA G GTAAATTGGAAGAGTTTGTTCAAGG aGGT-AGTGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTATACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGAACA 2293 AACTCTTCCAATTTAC CTGAATTATACCTCTTTGGCCGATTCA GAATTTTGTTGGCGTTTTCATGATCAAGAAAAAC ATAATTCA GGTAAATTG 2294 CAATTTAC C TGAATTAT 2295 Haemophilia BTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAA 2296 Lys5GluAGAGGTATAATTCAGGT A AATTGGAAGAGTTTGTTCAAGGGAA tAAA-GAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTCCCTTGA 2297 ACAAACTCTTCCAATT TACCTGAATTATACCTCTTTGGCCGATT CAGAATTTTGTTGGCGTTTTCATGATCAAGAAA ATTCAGGT AAATTGGAA 2298 TTCCAATT T ACCTGAAT 2299 Haemophilia BATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTA 2300 Glu7AlaTAATTCAGGTAAATTGG A AGAGTTTGTTCAAGGGAACCTTGAG GAA-GCAAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGATCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTT 2301 CCCTTGAACAAACTCT TCCAATTTACCTGAATTATACCTCTTTG GCCGATTCAGAATTTTGTTGGCGTTTTCATGAT TAAATTGG AAGAGTTTG 2302 CAAACTCT T CCAATTTA 2303 Haemophilia BGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAGAGG 2304 Glu7LysTATAATTCAGGTAAATTG G AAGAGTTTGTTCAAGGGAACCTTG gGAA-AAAAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTTC 2305 CCTTGAACAAACTCTT CCAATTTACCTGAATTATACCTCTTTGG CCGATTCAGAATTTTGTTGGCGTTTTCATGATC GTAAATTG GAAGAGTTT 2306 AAACTCTT C CAATTTAC 2307 Haemophilia BATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTA 2308 Glu7ValTAATTCAGGTAAATTGG A AGAGTTTGTTCAAGGGAACCTTGAG GAA-GTAAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGATCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAGGTT 2309 CCCTTGAACAAACTCT TCCAATTTACCTGAATTATACCTCTTTG GCCGATTCAGAATTTTGTTGGCGTTTTCATGAT TAAATTGG AAGAGTTTG 2310 CAAACTCT T CCAATTTA 2311 Haemophilia BATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAA 2312 Glu8AlaTTCAGGTAAATTGGAAG A GTTTGTTCAAGGGAACCTTGAGAG GAG-GCGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG 2313 GTTCCCTTGAACAAAC TCTTCCAATTTACCTGAATTATACCTCT TTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT ATTGGAAG AGTTTGTTC 2314 GAACAAAC T CTTCCAAT 2315 Haemophilia BATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAA 2316 Glu8GlyTTCAGGTAAATTGGAAG A GTTTGTTCAAGGGAACCTTGAGAG GAG-GGGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCAAG 2317 GTTCCCTTGAACAAAC TCTTCCAATTTACCTGAATTATACCTCT TTGGCCGATTCAGAATTTTGTTGGCGTTTTCAT ATTGGAAG AGTTTGTTC 2318 GAACAAAC T CTTCCAAT 2319 Haemophilia BAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTC 2320 Phe9CysAGGTAAATTGGAAGAGT T TGTTCAAGGGAACCTTGAGAGAGA TTT-TGTATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCACGCGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTC 2321 AAGGTTCCCTTGAACA AACTCTTCCAATTTACCTGAATTATAC CTCTTTGGCCGATTCAGAATTTTGTTGGCGTTTT GGAAGAGT TTGTTCAAG 2322 CTTGAACA A ACTCTTCC 2323 Haemophilia BGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATT 2324 Phe9IleCAGGTAAATTGGAAGAG T TTGTTCAAGGGAACCTTGAGAGAG gTTT-ATTAATGTATGGAAGAAAAGTGTAGTTTTGAAGAAGCACGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCTCTCTCA 2325 AGGTTCCCTTGAACAA ACTCTTCCAATTTACCTGAATTATACC TCTTTGGCCGATTCAGAATTTTGTTGGCGTTTTC TGGAAGAG TTTGTTCAA 2326 TTGAACAA A CTCTTCCA 2327 Haemophilia BTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATTC 2328 Arg(-1)SerTGAATCGGCCAAAGAG G TATAATTCAGGTAAATTGGAAGAGTT AGGt-AGCTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAATTCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCC 2329 AATTTACCTGAATTATA CCTCTTTGGCCGATTCAGAATTTTGTT GGCGTTTTCATGATCAAGAAAAACTGAAATGTAA CCAAAGAG GTATAATTC 2330 GAATTATA C CTCTTTGG 2331 Haemophilia BTTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAATT 2332 Arg(-1)ThrCTGAATCGGCCAAAGA G GTATAATTCAGGTAAATTGGAAGAG AGG-ACGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGATCCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCA 2333 ATTTACCTGAATTATAC CTCTTTGGCCGATTCAGAATTTTGTTG GCGTTTTCATGATCAAGAAAAACTGAAATGTAAA GCCAAAGA GGTATAATT 2334 AATTATAC C TCTTTGGC 2335 Haemophilia BCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCCAACAAAA 2336 Lys(-2)AsnTTCTGAATCGGCCAAA G AGGTATAATTCAGGTAAATTGGAAGA AAGa-AATGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGCATACATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAAT 2337 TTACCTGAATTATACCT CTTTGGCCGATTCAGAATTTTGTTGG CGTTTTCATGATCAAGAAAAACTGAAATGTAAAAG CGGCCAAA GAGGTATAA 2338 TTATACCT C TTTGGCCG 2339 Haemophilia BAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCC 2340 Arg(-4)GlnAACAAAATTCTGAATC G GCCAAAGAGGTATAATTCAGGTAAAT CGG-CAGTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGATCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG 2341 AATTATACCTCTTTGGC CGATTCAGAATTTTGTTGGCGTTTTCA TGATCAAGAAAAACTGAAATGTAAAAGAATAATT TCTGAATC GGCCAAAGA 2342 TCTTTGGC C GATTCAGA 2343 Haemophilia BAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGCC 2344 Arg(-4)LeuAACAAAATTCTGAATC G GCCAAAGAGGTATAATTCAGGTAAAT CGG-CTGTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGATCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTG 2345 AATTATACCTCTTTGGC CGATTCAGAATTTTGTTGGCGTTTTCA TGATCAAGAAAAACTGAAATGTAAAAGAATAATT TCTGAATC GGCCAAAGA 2346 TCTTTGGC C GATTCAGA 2347 Haemophilia BGAATTATTCTTTTACATTTCAGTTTTTCTTGATCATGAAAACGC 2348 Arg(-4)TrpCAACAAAATTCTGAAT C GGCCAAAGAGGTATAATTCAGGTAAA tCGG-TGGTTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGCTCTCTCAAGGTTCCCTTGAACAAACTCTTCCAATTTACCTGA 2349 ATTATACCTCTTTGGCC GATTCAGAATTTTGTTGGCGTTTTCAT GATCAAGAAAAACTGAAATGTAAAAGAATAATTC TTCTGAAT CGGCCAAAG 2350 CTTTGGCC G ATTCAGAA 2351 Haemophilia BGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTA 2352 Glni11TermAATTGGAAGAGTTTGTT C AAGGGAACCTTGAGAGAGAATGTAT tCAA-TAAGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGCTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACATTCT 2353 CTCTCAAGGTTCCCTT GAACAAACTCTTCCAATTTACCTGAAT TATACCTCTTTGGCCGATTCAGAATTTTGTTGGC AGTTTGTT CAAGGGAAC 2354 GTTCCCTT G AACAAACT 2355 Haemophilia BACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATT 2356 Gly12AlaGGAAGAGTTTGTTCAAG G GAACCTTGAGAGAGAATGTATGGA GGG-GCGAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACA 2357 TTCTCTCTCAAGGTTC CCTTGAACAAACTCTTCCAATTTACCT GAATTATACCTCTTTGGCCGATTCAGAATTTTGT TGTTCAAG GGAACCTTG 2358 CAAGGTTC C CTTGAACA 2359 Haemophilia BAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAAT 2360 Gly12ArgTGGAAGAGTTTGTTCAA G GGAACCTTGAGAGAGAATGTATGG aGGG-AGGAAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACAT 2361 TCTCTCTCAAGGTTCC CTTGAACAAACTCTTCCAATTTACCTG AATTATACCTCTTTGGCCGATTCAGAATTTTGTT TTGTTCAA GGGAACCTT 2362 AAGGTTCC C TTGAACAA 2363 Haemophilia BACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATT 2364 Gly12GluGGAAGAGTTTGTTCAAG G GAACCTTGAGAGAGAATGTATGGA GGG-GAGAGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTAAAACTTCTCGTGCTTCTTCAAAACTACACTTTTCTTCCATACA 2365 TTCTCTCTCAAGGTTC CCTTGAACAAACTCTTCCAATTTACCT GAATTATACCTCTTTGGCCGATTCAGAATTTTGT TGTTCAAG GGAACCTTG 2366 CAAGGTTC C CTTGAACA 2367 Haemophilia BCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC 2368 Glu17GlnAAGGGAACCTTGAGAGA G AATGTATGGAAGAAAAGTGTAGTT aGAA-CAATTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAATTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACAC 2369 TTTTCTTCCATACATT CTCTCTCAAGGTTCCCTTGAACAAACTC TTCCAATTTACCTGAATTATACCTCTTTGGCCG TTGAGAGA GAATGTATG 2370 CATACATT C TCTCTCAA 2371 Haemophilia BCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTC 2372 Glu17LysAAGGGAACCTTGAGAGA G AATGTATGGAAGAAAAGTGTAGTT aGAA-AAATTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAATTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTACAC 2373 TTTTCTTCCATACATT CTCTCTCAAGGTTCCCTTGAACAAACTC TTCCAATTTACCTGAATTATACCTCTTTGGCCG TTGAGAGA GAATGTATG 2374 CATACATT C TCTCTCAA 2375 Haemophilia BCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTTCAAG 2376 Cys18ArgGGAACCTTGAGAGAGAA T GTATGGAAGAAAAGTGTAGTTTTG aTGT-CGTAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAATTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACTA 2377 CACTTTTCTTCCATAC ATTCTCTCTCAAGGTTCCCTTGAACAA ACTCTTCCAATTTACCTGAATTATACCTCTTTGG AGAGAGAA TGTATGGAA 2378 TTCCATAC A TTCTCTCT 2379 Haemophilia BCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGG 2380 Cys18TyrGAACCTTGAGAGAGAAT G TATGGAAGAAAAGTGTAGTTTTGAA TGT-TATGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAACGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTCAAAACT 2381 ACACTTTTCTTCCATA CATTCTCTCTCAAGGTTCCCTTGAACAA ACTCTTCCAATTTACCTGAATTATACCTCTTTG GAGAGAAT GTATGGAAG 2382 CTTCCATA C ATTCTCTC 2383 Haemophilia BGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCT 2384 Glu20ValTGAGAGAGAATGTATGG A AGAAAAGTGTAGTTTTGAAGAAGC GAA-GTAACGAGAAGTTTTTGAAAACACTGAAAGAACAGTGAGCTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCTTC 2385 AAAACTACACTTTTCT TCCATACATTCTCTCTCAAGGTTCCCTT GAACAAACTCTTCCAATTTACCTGAATTATACC ATGTATGG AAGAAAAGT 2386 ACTTTTCT T CCATACAT 2387 Haemophilia BTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTG 2388 Glu21LysAGAGAGAATGTATGGAA G AAAAGTGTAGTTTTGAAGAAGCAC aGAA-AAAGAGAAGTTTTTGAAACACTGAAAGAACAGTGAGTATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGTGCTTCT 2389 TCAAAACTACACTTTT CTTCCATACATTCTCTCTCAAGGTTCCC TTGAACAAACTCTTCCAATTTACCTGAATTATA GTATGGAA GAAAAGTGT 2390 ACACTTTT C TTCCATAC 2391 Haemophilia BTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGA 2392 Cys23ArgGAATGTATGGAAGAAAAG T GTAGTTTTGAAGAAGCACGAGAA gTGT-CGTGTTTTTGAAAACACTGAAAGAACAGTGAGTATTTCCATGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTCGT 2393 GCTTCTTCAAAACTAC ACTTTTCTTCCATACATTCTCTCTCAAG GTTCCCTTGAACAAACTCTTCCAATTTACCTGA AAGAAAAG TGTAGTTTT 2394 AAAACTAC A CTTTTCTT 2395 Haemophilia BCAGGTAAAGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAG 2396 Cys23TyrAATGTATGGAAGAAAAGT G TAGTTTTGAAGAAGCACGAGAAGT TGT-TATTTTTGAAAACACTGAAAGAACAGTGAGTATTTCCACGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAACTTCTC 2397 GTGCTTCTTCAAAACTA CACTTTTCTTCCATACATTCTCTCTCA AGGTTCCCTTGAACAAACTCTTCCAATTTACCTG AGAAAAGT GTAGTTTTG 2398 CAAAACTA C ACTTTTCT 2399 Haemophilia BAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTAT 2400 Phe25SerGGAAGAAAAGTGTAGTT T TGAAGAAGCACGAGAAGTTTTTGAA TTT-TCTAACACTGAAAGAACAGTGAGTATTTCCACATAATATATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAAAC 2401 TTCTCGTGCTTCTTCA AAACTACACTTTTCTTCCATACATTCTC TCTCAAGGTTCCCTTGAACAAACTCTTCCAATT GTGTAGTT TTGAAGAAG 2402 CTTCTTCA A AACTACAC 2403 Haemophilia BTTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATG 2404 Glu26GlnGAAGAAAAGTGTAGTTTT G AAGAAGCACGAGAAGTTTTTGAAA tGAA-CAAACACTGAAAGAACAGTGAGTATTTCCACATAATACCGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTCAAAA 2405 ACTTCTCGTGCTTCTT CAAAACTACACTTTTCTTCCATACATTC TCTCTCAAGGTTCCCTTGAACAAACTCTTCCAA GTAGTTTT GAAGAAGCA 2406 TGCTTCTT C AAAACTAC 2407 Haemophilia BAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAG 2408 Glu27AlaAAAAGTGTAGTTTTGAAG A AGCACGAGAAGTTTTTGAAAACAC GAA-GCATGAAAGAACAGTGAGTATTTCCACATAATACCCTTCGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTT 2409 CAAAAACTTCTCGTGCT TCTTCAAAACTACACTTTTCTTCCATA CATTCTCTCTCAAGGTTCCCTTGAACAAACTCTT TTTTGAAG AAGCACGAG 2410 CTCGTGCT T CTTCAAAA 2411 Haemophilia BAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGA 2412 Glu27AspAAAGTGTAGTTTTGAAGA A GCACGAGAAGTTTTTGAAAACACT GAAg-GACGAAAGAACAGTGAGTATTTCCACATAATACCCTTCATGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTT 2413 TCAAAAACTTCTCGTGC TTCTTCAAAACTACACTTTTCTTCCAT ACATTCTCTCTCAAGGTTCCCTTGAACAAACTCT TTTGAAGA AGCACGAGA 2414 TCTCGTGC T TCTTCAAA 2415 Haemophilia BGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAA 2416 Glu27LysGAAAAGTGTAGTTTTGAA G AAGCACGAGAAGTTTTTGAAAACA aGAA-AAACTGAAAGAACAGTGAGTATTTCCACATAATACCCTTAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTTC 2417 AAAAACTTCTCGTGCTT CTTCAAAACTACACTTTTCTTCCATAC ATTCTCTCTCAAGGTTCCCTTGAACAAACTCTTC GTTTTGAA GAAGCACGA 2418 TCGTGCTT C TTCAAAAC 2419 Haemophilia BAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAG 2420 Glu27ValAAAAGTGTAGTTTTGAAG A AGCACGAGAAGTTTTTGAAAACAC GAA-GTATGAAAGAACAGTGAGTATTTCCACATAATACCCTTCGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGTGTTTT 2421 CAAAAACTTCTCGTGCT TCTTCAAAACTACACTTTTCTTCCATA CATTCTCTCTCAAGGTTCCCTTGAACAAACTCTT TTTTGAAG AAGCACGAG 2422 CTCGTGCT T CTTCAAAA 2423 Haemophiiia BTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT 2424 Arg29GlnGTAGTTTTGAAGAAGCAC G AGAAGTTTTTGAAAACACTGAAAG CGA-CAAAACAGTGAGTATTTCCACATAATACCCTTCAGATGCGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAG 2425 TGTTTTCAAAAACTTCT CGTGCTTCTTCAAAACTACACTTTTCT TCCATACATTCTCTCTCAAGGTTCCCTTGAACAA AGAAGCAC GAGAAGTTT 2426 AAACTTCT C GTGCTTCT 2427 Haemophilia BTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT 2428 Arg29ProGTAGTTTTGAAGAAGCAC G AGAAGTTTTTGAAAACACTGAAAG CGA-CCAAACAGTGAGTATTTCCACATAATACCCTTCAGATGCGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAG 2429 TGTTTTCAAAACTTCT CGTGCTTCTTCAAAACTACACTTTTCT TCCATACATTCTCTCTCAAGGTTCCCTTGAACAA AGAAGCAC GAGAAGTTT 2430 AAACTTCT C GTGCTTCT 2431 Haemophilia BTTTGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGT 2432 Arg29TermGTAGTTTTGAAGAAGCA C GAGAAGTTTTTGAAAACACTGAAAG aCGA-TGAAACAGTGAGTATTTCCACATAATACCCTTCAGATGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTCAGT 2433 GTTTTCAAAAACTTCTC GTGCTTCTTCAAAACTACACTTTTCTT CCATACATTCTCTCTCAAGGTTCCCTTGAACAAA AAGAAGCA CGAGAAGTT 2434 AACTTCTC G TGCTTCTT 2435 Haemophilia BGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGT 2436 Glu30LysAGTTTTGAAGAAGCACGA G AAGTTTTTGAAAACACTGAAAGAA aGAA-AAACAGTGAGTATTTCCACATAATACCCTTCAGATGCAGCTGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTC 2437 AGTGTTTTCAAAAACTT CTCGTGCTTCTTCAAAACTACACTTTT CTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC AAGCACGA GAAGTTTTT 2438 AAAAACTT C TCGTGCTT 2439 Haemophilia BGTTCAAGGGAACCTTGAGAGAGAATGTATGGAAGAAAAGTGT 2440 Glu30TermAGTTTTGAAGAAGCACGA G AAGTTTTTGAAAACACTGAAAGAA aGAA-TAACAGTGAGTATTTCCACATAATACCCTTCAGATGCAGCTGCATCTGAAGGGTATTATGTGGAAATACTCACTGTTCTTTC 2441 AGTGTTTTCAAAAACTT CTCGTGCTTCTTCAAAACTACACTTTT CTTCCATACATTCTCTCTCAAGGTTCCCTTGAAC AAGCACGA GAAGTTTTT 2442 AAAAACTT C TCGTGCTT 2443 Haemophilia BCCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAGAA 2444 Glu33AspGCACGAGAAGTTTTTGA A AACACTGAAAGAACAGTGAGTATTT GAAa-GACCCACATAATACCCTTCAGATGCAGAGCATAGAATATATTCTATGCTCTGCATCTGAAGGGTATTATGTGGAAATACTC 2445 ACTGTTCTTTCAGTGTT TTCAAAAACTTCTCGTGCTTCTTCAAA ACTACACTTTTCTTCCATACATTCTCTCTCAAGG GTTTTTGA AAACACTGA 2446 TCAGTGTT T TCAAAAAC 2447 Haemophilia BAACCTTGAGAGAGAATGTATGGAAGAAAAGTGTAGTTTTGAAG 2448 Glu33TermAAGCACGAGAAGTTTTT G AAAACACTGAAAGAACAGTGAGTAT tGAA-TAATTCCACATAATACCCTTCAGATGCAGAGCATAGAATTCTATGCTCTGCATCTGAAGGGTATTATGTGGAAATACTCAC 2449 TGTTCTTTCAGTGTTTT CAAAAACTTCTCGTGCTTCTTCAAAAC TACACTTTTCTTCCATACATTCTCTCTCAAGGTT AAGTTTTT GAAAACACT 2450 AGTGTTTT C AAAAACTT 2451 Haemophilia BCAAAACACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTT 2452 Trp42TermTATAGACTGAATTTT G GAAGCAGTATGTTGGTAAGCAATTCAT TGG-TAGTTTATCCTCTAGCTAATATATGAAACATATGAGCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAATTGCTT 2453 ACCAACATACTGCTTC CAAAATTCAGTCTATAAAGAATAAAAG AAGACAAATTAACGGTAATATCTAAAGTGTTTTG TGAATTTT GGAAGCAGT 2454 ACTGCTTC C AAAATTCA 2455 Haemophilia BAAACACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTTTA 2456 Lys43GluTAGACTGAATTTTGG A AGCAGTATGTTGGTAAGCAATTCATTT gAAG-GAGTATCCTCTAGCTAATATATGAAACATATGAGAATTCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAATTGC 2457 TTACCAACATACTGCT TCCAAAATTCAGTCTATAAAGAATAAAA GAAGACAAATTAACGGTAATATCTAAAGTGTTT AATTTTGG AAGCAGTAT 2458 ATACTGCT T CCAAAATT 2459 Haemophilia BCACTTTAGATATTACCGTTAATTTGTCTTCTTTTATTCTTTATAG 2460 Gln44TermACTGAATTTTGGAAG C AGTATGTTGGTAAGCAATTCATTTTATC gCAG-TAGCTCTAGCTAATATATGAAACATATGAGAATTATAATTCTCATATGTTTCATATATTAGCTAGAGGATAAAATGAAT 2461 TGCTTACCAACATACT GCTTCCAAAATTCAGTCTATAAAGAATA AAAGAAGACAAATTAACGGTAATATCTAAAGTG TTTGGAAG CAGTATGTT 2462 AACATACT G CTTCCAAA 2463 Haemophilia BCCGGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAAC 2464 Asp49GlyCTATCTCAAAGATGGAG A TCAGTGTGAGTCCAATCCATGTTTA GAT-GGTAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACATG 2465 GATTGGACTCACACTGA TCTCCATCTTTGAGATAGGTTAAGAA ATTGAATTGGCACGTAAACTGCTTAGAATGCCCGG AGATGGAG ATCAGTGTG 2466 CACACTGA T CTCCATCT 2467 Haemophilia BGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATC 2468 Gln50HisTCAAAGATGGAGATCA G TGTGAGTCCAATCCATGTTTAAATGG CAGt-CACCGGCAGTTGCAAGGATGACATTAATTCCTATGAATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAA 2469 CATGGATTGGACTCACA CTGATCTCCATCTTTGAGATAGGTTA AGAAATTGAATTGGCACGTAAACTGCTTAGAATGC GGAGATCA GTGTGAGTC 2470 GACTCACA C TGATCTCC 2471 Haemophilia BGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTA 2472 Gln50ProTCTCAAAGATGGAGATC A GTGTGAGTCCAATCCATGTTTAAAT CAG-CCGGGCGGCAGTTGCAAGGATGACATTAATTCCTATGATCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAAC 2473 ATGGATTGGACTCACAC TGATCTCCATCTTTGAGATAGGTTAA GAAATTGAATTGGCACGTAAACTGCTTAGAATGCC TGGAGATC AGTGTGAGT 2474 ACTCACAC T GATCTCCA 2475 Haemophilia BGGGCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCT 2476 Gln50TermATCTCAAAGATGGAGAT C AGTGTGAGTCCAATCCATGTTTAAA tCAG-TAGTGGCGGCAGTTGCAAGGATGACATTAATTCCTATGCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAAACA 2477 TGGATTGGACTCACACT GATCTCCATCTTTGAGATAGGTTAAG AAATTGAATTGGCACGTAAACTGCTTAGAATGCCC ATGGAGAT CAGTGTGAG 2478 CTCACACT G ATCTCCAT 2479 Haemophilia BCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCT 2480 Cys51ArgCAAAGATGGAGATCAG T GTGAGTCCAATCCATGTTTAAATGG gTGT-CGTCGGCAGTTGCAAGGATGACATTAATTCCTATGAATATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAA 2481 ACATGGATTGGACTCAC ACTGATCTCCATCTTTGAGATAGGTT AAGAAATTGAATTGGCACGTAAACTGCTTAGAATG GAGATCAG TGTGAGTCC 2482 GGACTCAC A CTGATCTC 2483 Haemophilia BCATTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCT 2484 Cys51SerCAAAGATGGAGATCAG T GTGAGTCCAATCCATGTTTAAATGG gTGT-AGTCGGCAGTTGCAAGGATGACATTAATTCCTATGAATATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTTAA 2485 ACATGGATTGGACTCAC ACTGATCTCCATCTTTGAGATAGGTT AAGAAATTGAATTGGCACGTAAACTGCTTAGAATG GAGATCAG TGTGAGTCC 2486 GGACTCAC A CTGATCTC 2487 Haemophilia BTTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCTCA 2488 Cys51TrpAAGATGGAGATCAGTG T GAGTCCAATCCATGTTTAAATGGCG TGTg-TGGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATTT 2489 AAACATGGATTGGACTC ACACTGATCTCCATCTTTGAGATAGG TTAAGAAATTGAATTGGCACGTAAACTGCTTAGAA GATCAGTG TGAGTCCAA 2490 TTGGACTC A CACTGATC 2491 Haemophilia BTCTAAGCAGTTTACGTGCCAATTCAATTTCTTAACCTATCTCAA 2492 Glu52TermAGATGGAGATCAGTGT G AGTCCAATCCATGTTTAAATGGCGG tGAG-TAGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTAACATTCATAGGAATTAATGTCATCCTTGCAACTGCCGCCATT 2493 TAAACATGGATTGGACT CACACTGATCTCCATCTTTGAGATAG GTTAAGAAATTGAATTGGCACGTAAACTGCTTAGA ATCAGTGT GAGTCCAAT 2494 ATTGGACT C ACACTGAT 2495 Haemophilia BTTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAG 2496 Pro55AlaATCAGTGTGAGTCCAAT C CATGTTTAAATGGCGGCAGTTGCA tCCA-GCAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACT 2497 GCCGCCATTTAAACATG GATTGGACTCACACTGATCTCCATCT TTGAGATAGGTTAAGAAATTGAATTGGCACGTAAA AGTCCAAT CCATGTTTA 2498 TAAACATG G ATTGGACT 2499 Haemophilia BTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA 2500 Pro55ArgTCAGTGTGAGTCCAATC C ATGTTTAAATGGCGGCAGTTGCAA CCA-CGAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTTAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC 2501 TGCCGCCATTTAAACAT GGATTGGACTCACACTGATCTCCATC TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA GTCCAATC CATGTTTAA 2502 TTAAACAT G GATTGGAC 2503 Haemophilia BTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA 2504 Pro55GlnTCAGTGTGAGTCCAATC C ATGTTTAAATGGCGGCAGTTGCAA CCA-CAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTTAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC 2505 TGCCGCCATTTAAACAT GGATTGGACTCACACTGATCTCCATC TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA GTCCAATC CATGTTTAA 2506 TTAAACAT G GATTGGAC 2507 Haemophilia BTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGA 2508 Pro55LeuTCAGTGTGAGTCCAATC C ATGTTTAAATGGCGGCAGTTGCAA CCA-CTAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTTAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAAC 2509 TGCCGCCATTTAAACAT GGATTGGACTCACACTGATCTCCATC TTTGAGATAGGTTAAGAAATTGAATTGGCACGTAA GTCCAATC CATGTTTAA 2510 TTAAACAT G GATTGGAC 2511 Haemophilia BTTTACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAG 2512 Pro55SerATCAGTGTGAGTCCAAT C CATGTTTAAATGGCGGCAGTTGCA tCCA-TCAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCAACT 2513 GCCGCCATTTAAACATG GATTGGACTCACACTGATCTCCATCT TTGAGATAGGTTAAGAAATTGAATTGGCACGTAAA AGTCCAAT CCATGTTTA 2514 TAAACATG G ATTGGACT 2515 Haemophilia BACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATC 2516 Cys56ArgAGTGTGAGTCCAATCCA T GTTTAAATGGCGGCAGTTGCAAGG aTGT-CGTATGACATTAATTCCTATGAATGTTGGTGTCCCTTTGCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCA 2517 ACTGCCGCCATTTAAAC ATGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACGT CCAATCCA TGTTTAAAT 2518 ATTTAAAC A TGGATTGG 2519 Haemophilia BACGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATC 2520 Cys56SerAGTGTGAGTCCAATCCA T GTTTAAATGGCGGCAGTTGCAAGG aTGT-AGTATGACATTAATTCCTATGAATGTTGGTGTCCCTTTGCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGCA 2521 ACTGCCGCCATTTAAAC ATGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACGT CCAATCCA TGTTTAAAT 2522 ATTTAAAC A TGGATTGG 2523 Haemophilia BCGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATCA 2524 Cys56SerGTGTGAGTCCAATCCAT G TTTAAATGGCGGCAGTTGCAAGGA TGT-TCTTGACATTAATTCCTATGAATGTTGGTGTCCCTTTGGCCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC 2525 AACTGCCGCCATTTAAA CATGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACG CAATCCAT GTTTAAATG 2526 CATTTAAA C ATGGATTG 2527 Haemophilia BCGTGCCAATTCAATTTCTTAACCTATCTCAAAGATGGAGATCA 2528 Cys56TyrGTGTGAGTCCAATCCAT G TTTAAATGGCGGCAGTTGCAAGGA TGT-TATTGACATTAATTCCTATGAATGTTGGTGTCCCTTTGGCCAAAGGGACACCAACATTCATAGGAATTAATGTCATCCTTGC 2529 AACTGCCGCCATTTAAA CATGGATTGGACTCACACTGATCTCC ATCTTTGAGATAGGTTAAGAAATTGAATTGGCACG CAATCCAT GTTTAAATG 2530 CATTTAAA C ATGGATTG 2531 Haemophilia BATTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAG 2532 Asn58LysTCCAATCCATGTTTAAA T GGCGGCAGTTGCAAGGATGACATTA AATg-AAGATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAATTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTCA 2533 TCCTTGCAACTGCCGCC ATTTAAACATGGATTGGACTCACACT GATCTCCATCTTTGAGATAGGTTAAGAAATTGAAT TGTTTAAA TGGCGGCAG 2534 CTGCCGCC A TTTAAACA 2535 Haemophilia BTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTC 2536 Gly59AspCAATCCATGTTTAAATG G CGGCAGTTGCAAGGATGACATTAAT GGC-GACTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGT 2537 CATCCTTGCAACTGCCG CCATTTAAACATGGATTGGACTCACA CTGATCTCCATCTTTGAGATAGGTTAAGAAATTGA TTTAAATG GCGGCAGTT 2538 AACTGCCG C CATTTAAA 2539 Haemophilia BTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTC 2540 Gly59ValCAATCCATGTTTAAATG G CGGCAGTTGCAAGGATGACATTAAT GGC-GTCTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGT 2541 CATCCTTGCAACTGCCG CCATTTAAACATGGATTGGACTCACA CTGATCTCCATCTTTGAGATAGGTTAAGAAATTGA TTTAAATGGCGGCAGTT 2542 AACTGCCG C CATTTAAA 2543 Haemophilia BTTCAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGT 2544 Gly59SerCCAATCCATGTTTAAAT G GCGGCAGTTGCAAGGATGACATTAA tGGC-AGCTTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAATGTC 2545 ATCCTTGCAACTGCCGC CATTTAAACATGGATTGGACTCACAC TGATCTCCATCTTTGAGATAGGTTAAGAAATTGAA GTTTAAAT GGCGGCAGT 2546 ACTGCCGC C ATTTAAAC 2547 Haemophilia BAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA 2548 Gly60SerATCCATGTTTAAATGGC G GCAGTTGCAAGGATGACATTAATTC cGGC-AGCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAATTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT 2549 GTCATCCTTGCAACTGC CGCCATTTAAACATGGATTGGACTCA CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT TAAATGGC GGCAGTTGC 2550 GCAACTGC C GCCATTTA 2551 Haemophilia BAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA 2552 Gly60CysATCCATGTTTAAATGGC G GCAGTTGCAAGGATGACATTAATTC cGGC-TGCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAATTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT 2553 GTCATCCTTGCAACTGC CGCCATTTAAACATGGATTGGACTCA CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT TAAATGGC GGCAGTTGC 2554 GCAACTGC C GCCATTTA 2555 Haemophilia BATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAA 2556 Gly60AspTCCATGTTTAAATGGCG G CAGTTGCAAGGATGACATTAATTCC GGC-GACTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAATTTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAA 2557 TGTCATCCTTGCAACTG CCGCCATTTAAACATGGATTGGACTC ACACTGATCTCCATCTTTGAGATAGGTTAAGAAAT AAATGGCG GCAGTTGCA 2558 TGCAACTG C CGCCATTT 2559 Haemophilia BAATTTCTTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCA 2560 Gly60ArgATCCATGTTTAAATGGC G GCAGTTGCAAGGATGACATTAATTC cGGC-CGCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAATTCCTTCAAATCCAAAGGGACACCAACATTCATAGGAATTAAT 2561 GTCATCCTTGCAACTGC CGCCATTTAAACATGGATTGGACTCA CACTGATCTCCATCTTTGAGATAGGTTAAGAAATT TAAATGGC GGCAGTTGC 2562 GCAACTGC C GCCATTTA 2563 Haemophilia BTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATG 2564 Cys62TyrTTTAAATGGCGGCAGTT G CAAGGATGACATTAATTCCTATGAA TGC-TACTGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGCAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGG 2565 AATTAATGTCATCCTTG CAACTGCCGCCATTTAAACATGGATT GGACTCACACTGATCTCCATCTTTGAGATAGGTTA CGGCAGTT GCAAGGATG 2566 CATCCTTG C AACTGCCG 2567 Haemophilia BTAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATG 2568 Cys62SerTTTAAATGGCGGCAGTT G CAAGGATGACATTAATTCCTATGAA TGC-TCCTGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGCAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAGG 2569 AATTAATGTCATCCTTG CAACTGCCGCCATTTAAACATGGATT GGACTCACACTGATCTCCATCTTTGAGATAGGTTA CGGCAGTT GCAAGGATG 2570 CATCCTTG C AACTGCCG 2571 Haemophilia BAACCTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGT 2572 Cys62TermTTAAATGGCGGCAGTTG C AAGGATGACATTAATTCCTATGAAT TGCa-TGAGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTCATAG 2573 GAATTAATGTCATCCTT GCAACTGCCGCCATTTAAACATGGAT TGGACTCACACTGATCTCCATCTTTGAGATAGGTT GGCAGTTG CAAGGATGA 2574 TCATCCTT G CAACTGCC 2575 Haemophilia BTCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAAT 2576 Asp64GluGGCGGCAGTTGCAAGGA T GACATTAATTCCTATGAATGTTGG GATg-GAGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTATAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACAT 2577 TCATAGGAATTAATGTC ATCCTTGCAACTGCCGCCATTTAAAC ATGGATTGGACTCACACTGATCTCCATCTTTGAGA TGCAAGGA TGACATTAA 2578 TTAATGTC A TCCTTGCA 2579 Haemophilia BATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAA 2580 Asp64GlyTGGCGGCAGTTGCAAGG A TGACATTAATTCCTATGAATGTTG GAT-GGTGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATT 2581 CATAGGAATTAATGTCA TCCTTGCAACTGCCGCCATTTAAACA TGGATTGGACTCACACTGATCTCCATCTTTGAGAT TTGCAAGG ATGACATTA 2582 TAATGTCA TCCTTGCAA 2583 Haemophilia BTATCTCAAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAA 2584 Asp64AsnATGGCGGCAGTTGCAAG G ATGACATTAATTCCTATGAATGTTG gGAT-AATGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACCAACATTC 2585 ATAGGAATTAATGTCAT CCTTGCAACTGCCGCCATTTAAACAT GGATTGGACTCACACTGATCTCCATCTTTGAGATA GTTGCAAG GATGACATT 2586 AATGTCAT C CTTGCAAC 2587 Haemophilia BAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG 2588 Ile66SerGCAGTTGCAAGGATGACA T TAATTCCTATGAATGTTGGTGTCC ATT-AGTCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAATTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACC 2589 AACATTCATAGGAATTA ATGTCATCCTTGCAACTGCCGCCATT TAAACATGGATTGGACTCACACTGATCTCCATCTT GGATGACA TTAATTCCT 2590 AGGAATTA A TGTCATCC 2591 Haemophilia BAAGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCG 2592 Ile66ThrGCAGTTGCAAGGATGACA T TAATTCCTATGAATGTTGGTGTCC ATT-ACTCTTTGGATTTGAAGGAAAGAACTGTGAATTAGGTAATTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGACACC 2593 AACATTCATAGGAATTA ATGTCATCCTTGCAACTGCCGCCATT TAAACATGGATTGGACTCACACTGATCTCCATCTT GGATGACA TTAATTCCT 2594 AGGAATTA A TGTCATCC 2595 Haemophilia BTGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAG 2596 Asn67LysTTGCAAGGATGACATTAA T TCCTATGAATGTTGGTGTCCCTTT AATt-AAAGGATTTGAAGGAAAGAACTGTGAATTAGGTAAGTAATTACTTACCTAATTCACAGTTCTTTCCTTCAAATCCAAAGGGAC 2597 ACCAACATTCATAGGA ATTAATGTCATCCTTGCAACTGCCGCC ATTTAAACATGGATTGGACTCACACTGATCTCCA GACATTAA TTCCTATGA 2598 TCATAGGA A TTAATGTC 2599 Haemophilia BATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCA 2600 Tyr69CysAGGATGACATTAATTCCT A TGAATGTTGGTGTCCCTTTGGATT TAT-TGTTGAAGGAAAGAACTGTGAATTAGGTAAGTAACTATTAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAATCCAAA 2601 GGGACACCAACATTCA TAGGAATTAATGTCATCCTTGCAACTG CCGCCATTTAAACATGGATTGGACTCACACTGAT TAATTCCT ATGAATGTT 2602 AACATTCA T AGGAATTA 2603 Haemophilia BTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGA 2604 Cys71TermCATTAATTCCTATGAATG T TGGTGTCCCTTTGGATTTGAAGGA TGTt-TGAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGAATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAA 2605 ATCCAAAGGGACACCA ACATTCATAGGAATTAATGTCATCCTT GCAACTGCCGCCATTTAAACATGGATTGGACTCA TATGAATG TTGGTGTCC 2606 GGACACCA A CATTCATA 2607 Haemophilia BGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATG 2608 Cys71SerACATTAATTCCTATGAAT G TTGGTGTCCCTTTGGATTTGAAGG TGT-TCTAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGATCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAA 2609 TCCAAAGGGACACCAA CATTCATAGGAATTAATGTCATCCTTG CAACTGCCGCCATTTAAACATGGATTGGACTCAC CTATGAAT GTTGGTGTC 2610 GACACCAA C ATTCATAG 2611 Haemophilia BGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATG 2612 Cys71TyrACATTAATTCCTATGAAT G TTGGTGTCCCTTTGGATTTGAAGG TGT-TATAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGATCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAA 2613 TCCAAAGGGACACCAA CATTCATAGGAATTAATGTCATCCTTG CAACTGCCGCCATTTAAACATGGATTGGACTCAC CTATGAAT GTTGGTGTC 2614 GACACCAA C ATTCATAG 2615 Haemophilia BTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGAT 2616 Cys71SerGACATTAATTCCTATGAA T GTTGGTGTCCCTTTGGATTTGAAG aTGT-AGTGAAAGAACTGTGAATTAGGTAAGTAACTATTTTTTGCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCAAAT 2617 CCAAAGGGACACCAAC ATTCATAGGAATTAATGTCATCCTTGC AACTGCCGCCATTTAAACATGGATTGGACTCACA CCTATGAA TGTTGGTGT 2618 ACACCAAC A TTCATAGG 2619 Haemophilia BGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGAC 2620 Trp72ArgATTAATTCCTATGAATGT T GGTGTCCCTTTGGATTTGAAGGAA tTGG-AGGAGAACTGTGAATTAGGTAAGTAACTATTTTTTGAATATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTTCA 2621 AATCCAAAGGGACACC AACATTCATAGGAATTAATGTCATCCT TGCAACTGCCGCCATTTAAACATGGATTGGACTC ATGAATGT TGGTGTCCC 2622 GGGACACC A ACATTCAT 2623 Haemophilia BGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACAT 2624 Trp72TermTAATTCCTATGAATGTTG G TGTCCCTTTGGATTTGAAGGAAAG TGGt-TGAAACTGTGAATTAGGTAAGTAACTATTTTTTGAATACGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCTT 2625 CAAATCCAAAGGGACA CCAACATTCATAGGAATTAATGTCATC CTTGCAACTGCCGCCATTTAAACATGGATTGGAC GAATGTTG GTGTCCCTT 2626 AAGGGACA C CAACATTC 2627 Haemophilia BCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA 2628 Cys73TyrTTCCTATGAATGTTGGT G TCCCTTTGGATTTGAAGGAAAGAAC TGT-TATTGTGAATTAGGTAAGTAACTATTTTTTGAATACTCGAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCC 2629 TTCAAATCCAAAGGGA CACCAACATTCATAGGAATTAATGTCA TCCTTGCAACTGCCGCCATTTAAACATGGATTGG ATGTTGGT GTCCCTTTG 2630 CAAAGGGA C ACCAACAT 2631 Haemophilia BTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTA 2632 Cys73ArgATTCCTATGAATGTTGG T GTCCCTTTGGATTTGAAGGAAAGAA gTGT-CGTCTGTGAATTAGGTAAGTAACTATTTTTTGAATACTAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCCT 2633 TCAAATCCAAAGGGAC ACCAACATTCATAGGAATTAATGTCAT CCTTGCAACTGCCGCCATTTAAACATGGATTGGA AATGTTGG TGTCCCTTT 2634 AAAGGGAC A CCAACATT 2635 Haemophilia BCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAA 2636 Cys73PheTTCCTATGAATGTTGGT G TCCCTTTGGATTTGAAGGAAAGAAC TGT-TTTTGTGAATTAGGTAAGTAACTATTTTTTGAATACTCGAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTCC 2637 TTCAAATCCAAAGGGA CACCAACATTCATAGGAATTAATGTCA TCCTTGCAACTGCCGCCATTTAAACATGGATTGG ATGTTGGT GTCCCTTTG 2638 CAAAGGGA C ACCAACAT 2639 Haemophilia BCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAAT 2640 Cys73TermTCCTATGAATGTTGGTG T CCCTTTGGATTTGAAGGAAAGAACT TGTc-TGAGTGAATTAGGTAAGTAACTATTTTTTGAATACTCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACAGTTCTTTC 2641 CTTCAAATCCAAAGGG ACACCAACATTCATAGGAATTAATGTC ATCCTTGCAACTGCCGCCATTTAAACATGGATTG TGTTGGTG TCCCTTTGG 2642 CCAAAGGG A CACCAACA 2643 Haemophilia BGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGA 2644 Gly76ValATGTTGGTGTCCCTTTG G ATTTGAAGGAAAGAACTGTGAATTA GGA-GTAGGTAAGTAACTATTTTTTGAATACTCATGGTTCAATTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACA 2645 GTTCTTTCCTTCAAAT CCAAAGGGACACCAACATTCATAGGAA TTAATGTCATCCTTGCAACTGCCGCCATTTAAAC TCCCTTTG GATTTGAAG 2646 CTTCAAAT C CAAAGGGA 2647 Haemophilia BTGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATG 2648 Gly76ArgAATGTTGGTGTCCCTTT G GATTTGAAGGAAAGAACTGTGAATT tGGA-AGAAGGTAAGTAACTATTTTTTGAATACTCATGGTTCATGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTCACAG 2649 TTCTTTCCTTCAAATC CAAAGGGACACCAACATTCATAGGAAT TAATGTCATCCTTGCAACTGCCGCCATTTAAACA GTCCCTTT GGATTTGAA 2650 TTCAAATC C AAAGGGAC 2651 Haemophilia BTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG 2652 Phe77CysTTGGTGTCCCTTTGGAT T TGAAGGAAAGAACTGTGAATTAGGT TTT-TGTAAGTAACTATTTTTTGAATACTCATGGTTCAAAGTACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC 2653 ACAGTTCTTTCCTTCA AATCCAAAGGGACACCAACATTCATAG GAATTAATGTCATCCTTGCAACTGCCGCCATTTA CTTTGGAT TTGAAGGAA 2654 TTCCTTCA A ATCCAAAG 2655 Haemophilia BTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG 2656 Phe77SerTTGGTGTCCCTTTGGAT T TGAAGGAAAGAACTGTGAATTAGGT TTT-TCTAAGTAACTATTTTTTGAATACTCATGGTTCAAAGTACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC 2657 ACAGTTCTTTCCTTCA AATCCAAAGGGACACCAACATTCATAG GAATTAATGTCATCCTTGCAACTGCCGCCATTTA CTTTGGAT TTGAAGGAA 2658 TTCCTTCA A ATCCAAAG 2659 Haemophilia BTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATG 2660 Phe77TyrTTGGTGTCCCTTTGGAT T TGAAGGAAAGAACTGTGAATTAGGT TTT-TATAAGTAACTATTTTTTGAATACTCATGGTTCAAAGTACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAATTC 2661 ACAGTTCTTTCCTTCA AATCCAAAGGGACACCAACATTCATAG GAATTAATGTCATCCTTGCAACTGCCGCCATTTA CTTTGGAT TTGAAGGAA 2662 Haemophilia B TTCCTTCA A ATCCAAAG 2663AATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTT 2664 Glu78LysGGTGTCCCTTTGGATTT G AAGGAAAGAACTGTGAATTAGGTAA tGAA-AAAGTAACTATTTTTTGAATACTCATGGTTCAAAGTTTAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACCTAAT 2665 TCACAGTTCTTTCCTT CAAATCCAAAGGGACACCAACATTCAT AGGAATTAATGTCATCCTTGCAACTGCCGCCATT TTGGATTT GAAGGAAAG 2666 CTTTCCTT C AAATCCAA 2667 Haemophilia BGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGT 2668 Gly79ValGTCCCTTTGGATTTGAAG G AAAGAACTGTGAATTAGGTAAGTA GGA-GTAACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCTAGGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTAC 2669 CTAATTCACAGTTCTTT CCTTCAAATCCAAAGGGACACCAACA TTCATAGGAATTAATGTCATCCTTGCAACTGCCGC ATTTGAAG GAAAGAACT 2670 AGTTCTTT C CTTCAAAT 2671 Haemophilia BGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGG 2672 Gly79ArgTGTCCCTTTGGATTTGAA G GAAAGAACTGTGAATTAGGTAAGT aGGA-AGAAACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCGGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTACC 2673 TAATTCACAGTTCTTTC CTTCAAATCCAAAGGGACACCAACAT TCATAGGAATTAATGTCATCCTTGCAACTGCCGCC GATTTGAA GGAAAGAAC 2674 GTTCTTTC C TTCAAATC 2675 Haemophilia BGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGT 2676 Gly79GluGTCCCTTTGGATTTGAAG G AAAGAACTGTGAATTAGGTAAGTA GGA-GAAACTATTTTTTGAATACTCATGGTTCAAAGTTTCCCTAGGGAAACTTTGAACCATGAGTATTCAAAAAATAGTTACTTAC 2677 CTAATTCACAGTTCTTT CCTTCAAATCCAAAGGGACACCAACA TTCATAGGAATTAATGTCATCCTTGCAACTGCCGC ATTTGAAG GAAAGAACT 2678 AGTTCTTT C CTTCAAAT 2679 Haemophilia BTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT 2680 Cys88SerCTTTTAGATGTAACAT G TAACATTAAGAATGGCAGATGCGAGC TGT-TCTAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGTACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC 2681 TGCCATTCTTAATGTTA CATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAA TGTAACAT GTAACATTA 2682 TAATGTTA C ATGTTACA 2683 Haemophilia BTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT 2684 Cys88PheCTTTTAGATGTAACAT G TAACATTAAGAATGGCAGATGCGAGC TGT-TTTAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGTACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC 2685 TGCCATTCTTAATGTTA CATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAA TGTAACAT GTAACATTA 2686 TAATGTTA C ATGTTACA 2687 Haemophilia BTTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCT 2688 Cys88ArgTCTTTTAGATGTAACA T GTAACATTAAGAATGGCAGATGCGAG aTGT-CGTCAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGCCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATCT 2689 GCCATTCTTAATGTTAC ATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAAA ATGTAACA TGTAACATT 2690 AATGTTAC A TGTTACAT 2691 Haemophilia BTTAGAAATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTT 2692 Cys88TyrCTTTTAGATGTAACAT G TAACATTAAGAATGGCAGATGCGAGC TGT-TATAGTTTTGTAAAAATAGTGCTGATAACAAGGTGGTACCACCTTGTTATCAGCACTATTTTTACAAAACTGCTCGCATC 2693 TGCCATTCTTAATGTTA CATGTTACATCTAAAAGAAGCAAAATA GACAGTAACAGCATCATTTAACATGCATTTCTAA TGTAACAT GTAACATTA 2694 TAATGTTA C ATGTTACA 2695 Haemophilia BATGCATGTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTA 2696 Ile90ThrGATGTAACATGTAACA T TAAGAATGGCAGATGCGAGCAGTTTT ATT-ACTGTAAAAATAGTGCTGATAACAAGGTGGTTTGCTCGAGCAAACCACCTTGTTATCAGCACTATTTTTACAAAACTGCT 2697 CGCATCTGCCATTCTTA ATGTTACATGTTACATCTAAAAGAAG CAAAATAGACAGTAACAGCATCATTTAACATGCAT ATGTAACA TTAAGAATG 2698 CATTCTTA A TGTTACAT 2699 Haemophilia BTGTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGT 2700 Asn92HisAACATGTAACATTAAG A ATGGCAGATGCGAGCAGTTTTGTAAA gAAT-CATAATAGTGCTGATAACAAGGTGGTTTGCTCCTGTATACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACAAAA 2701 CTGCTCGCATCTGCCAT TCTTAATGTTACATGTTACATCTAAAA GAAGCAAAATAGACAGTAACAGCATCATTTAACA ACATTAAG AATGGCAGA 2702 TCTGCCAT T CTTAATGT 2703 Haemophilia BTTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAA 2704 Asn92LysCATGTAACATTAAGAA T GGCAGATGCGAGCAGTTTTGTAAAAA AATg-AAATAGTGCTGATAACAAGGTGGTTTGCTCCTGTACTAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACAA 2705 AACTGCTCGCATCTGCC ATTCTTAATGTTACATGTTACATCTA AAAGAAGCAAAATAGACAGTAACAGCATCATTTAA ATTAAGAA TGGCAGATG 2706 CATCTGCC A TTCTTAAT 2707 Haemophilia BAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACA 2708 Gly93AspTGTAACATTAAGAATG G CAGATGCGAGCAGTTTTGTAAAAATA GGC-GACGTGCTGATAACAAGGTGGTTTGCTCCTGTACTGATCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTAC 2709 AAAACTGCTCGCATCTG CCATTCTTAATGTTACATGTTACATCT AAAAGAAGCAAAATAGACAGTAACAGCATCATTT TAAGAATG GCAGATGCG 2710 CGCATCTG C CATTCTTA 2711 Haemophilia BTAAATGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAAC 2712 Gly93SerATGTAACATTAAGAAT G GCAGATGCGAGCAGTTTTGAAAAAT tGGC-AGCAGTGCTGATAACAAGGTGGTTTGCTCCTGTACTGCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTTTTACA 2713 AAACTGCTCGCATCTGC CATTCTTAATGTTACATGTTACATCTA AAAGAAGCAAAATAGACAGTAACAGCATCATTTA TTAAGAAT GGCAGATGC 2714 GCATCTGC C ATTCTTAA 2715 Haemophilia BGATGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTA 2716 Arg94SerACATTAAGAATGGCAG A TGCGAGCAGTTTTGTAAAAATAGTGC AGAt-AGTTGATAACAAGGTGGTTTGCTCCTGTACTGAGGGATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTATTT 2717 TTACAAAACTGCTCGCA TCTGCCATTCTTAATGTTACATGTTAC ATCTAAAAGAAGCAAAATAGACAGTAACAGCATC AATGGCAG ATGCGAGCA 2718 TGCTCGCA T CTGCCATT 2719 Haemophilia BTGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAAC 2720 Cys95TyrATTAAGAATGGCAGAT G CGAGCAGTTTTGTAAAAATAGTGCTG TGC-TACATAACAAGGTGGTTTGCTCCTGTACTGAGGGATATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTAT 2721 TTTTACAAAACTGCTCG CATCTGCCATTCTTAATGTTACATGTT ACATCTAAAAGAAGCAAAATAGACAGTAACAGCA TGGCAGAT GCGAGCAGT 2722 ACTGCTCG C ATCTGCCA 2723 Haemophilia BGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACA 2724 Cys95TrpTTAAGAATGGCAGATG C GAGCAGTTTTGTAAAAATAGTGCTGA TGCg-TGGTAACAAGGTGGTTTGCTCCTGTACTGAGGGATATATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTA 2725 TTTTTACAAAACTGCTC GCATCTGCCATTCTTAATGTTACATGT TACATCTAAAAGAAGCAAAATAGACAGTAACAGC GGCAGATG CGAGCAGTT 2726 AACTGCTC G CATCTGCC 2727 Haemophilia BGCTGTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACA 2728 Cys95TermTTAAGAATGGCAGATG C GAGCAGTTTTGTAAAAATAGTGCTGA TGCg-TGATAACAAGGTGGTTTGCTCCTGTACTGAGGGATATATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAGCACTA 2729 TTTTTACAAAACTGCTC GCATCTGCCATTCTTAATGTTACATGT TACATCTAAAAGAAGCAAAATAGACAGTAACAGC GGCAGATG CGAGCAGTT 2730 AACTGCTC G CATCTGCC 2731 Haemophilia BTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTMCATTAAG 2732 Gln97ProAATGGCAGATGCGAGC A GTTTTGTAAAAATAGTGCTGATAACA GAG-CCGAGGTGGTTTGCTCCTGTACTGAGGGATATCGACTAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCA 2733 GCACTATTTTTACAAAAC TGCTCGCATCTGCCATTCTTAATGTT ACATGTTACATCTAAAAGAAGCAAATAGACAGTA ATGCGAGC AGTTTTGTA 2734 TACAAAAC T GCTCGCAT 2735 Haemophilia BTTACTGTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAA 2736 Gln97GluGAATGGCAGATGCGAG C AGTTTTGTAAAAATAGTGCTGATAAC gCAG-GAGAAGGTGGTTTGCTCCTGTACTGAGGGATATCGACGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGTTATCAG 2737 CACTATTTTTACAAAACT GCTCGCATCTGCCATTCTTAATGTTA CATGTTACATCTAAAAGAAGCAAAATAGACAGTAA GATGCGAG CAGTTTTGT 2738 ACAAAACT G CTCGCATC 2739 Haemophilia BTCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAGAATGG 2740 Cys99ArgCAGATGCGAGCAGTTT T GTAAAAATAGTGCTGATAACAAGGTG tTGT-CGTGTTTGCTCCTGTACTGAGGGATATCGACTTGCAGCTGCAAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTGT 2741 TATCAGCACTATTTTTAC AAAACTGCTCGCATCTGCCATTCTT AATGTTACATGTTACATCTAAAAGAAGCAAAATAGA AGCAGTTT TGTAAAAAT 2742 ATTTTTAC A AAACTGCT 2743 Haemophilia BCTATTTTGCTTCTTTTAGATGTAACATGTAACATTAAGAATGGC 2744 Cys99TyrAGATGCGAGCAGTTTT G TAAAAATAGTGCTGATAACAAGGTG TGT-TATGTTTGCTCCTGTACTGAGGGATATCGACTTGCAGATCTGCAAGTCGATATCCCTCAGTACAGGAGCAAACCACCTTG 2745 TTATCAGCACTATTTTTA CAAAACTGCTCGCATCTGCCATTCTT AATGTTACATGTTACATCTAAAAGAAGCAAAATAG GCAGTTTT GTAAAAATA 2746 TATTTTTA C AAAACTGC 2747 Warfarin sensitivityTTTTTTGCTAAAACTAAAGAATTATTCTTTTACATTTCAGTTTTT 2748 Ala(-10)ThrCTTGATCATGAAAAC G CCAACAAAATTCTGAATCGGCCAAAGA cGCC-ACCGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCCG 2749 ATTCAGAATTTTGTTGG CGTTTTCATGATCAAGAAAAACTGAAA TGTAAAAGAATAATTCTTTAGTTTTAGCAAAAAA ATGAAAAC GCCAACAAA 2750 TTTGTTGG C GTTTTCAT 2751 Warfarin sensitivityTTTTTGCTAAAACTAAAGAATTATTCTTTTACATTTCAGTTTTTC 2752 Ala(-10)ValTTGATCATGAAAACG C CAACAAAATTCTGAATCGGCCAAAGAG GCC-GTCGTATAATTCAGGTAAATTGGAAGAGTTTGTTCATGAACAAACTCTTCCAATTTACCTGAATTATACCTCTTTGGCC 2753 GATTCAGAATTTTGTTG GCGTTTTCATGATCAAGAAAAACTGA AATGTAAAAGAATAATTCTTTAGTTTTAGCAAAAA TGAAAACG CCAACAAAA 2754 TTTTGTTG G CGTTTTCA 2755 Haemophilia BTGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCCTCA 2756 Gly(-26)ValTCACCATCTGCCTTTTAG G ATATCTACTCAGTGCTGAATGTAC GGA-GTAAGGTTTGTTTCCTTTTTTAAAATACATTGAGTATGCGCATACTCAATGTATTTTAAAAAAGGAAACAAACCTGTACATTC 2757 AGCACTGAGTAGATAT CCTAAAAGGCAGATGGTGATGAGGCC TGGTGATTCTGCCATGATCATGTTCACGCGCTGCA CCTTTTAG GATATCTAC 2758 GTAGATAT C CTAAAAGG 2759 Haemophilia BTTATGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCC 2760 Leu(-27)TermTCATCACCATCTGCCTTT T AGGATATCTACTCAGTGCTGAATG TTA-TAATACAGGTTTGTTTCCTTTTTTAAAATACATTGAGTATACTCAATGTATTTTAAAAAAGGAAACAAACCTGTACATTCAGC 2761 ACTGAGTAGATATCCT AAAAGGCAGATGGTGATGAGGCCTGG TGATTCTGCCATGATCATGTTCACGCGCTGCATAA CTGCCTTT TAGGATATC 2762 GATATCCT A AAAGGCAG 2763 Haemophilia BTAGCAAAGGTTATGCAGCGCGTGAACATGATCATGGCAGAAT 2764 Ile(-30)AsnCACCAGGCCTCATCACCA T CTGCCTTTTAGGATATCTACTCAG ATC-AACTGCTGAATGTACAGGTTTGTTTCCTTTTTTAAAATATATTTTAAAAAAGGAAACAAACCTGTACATTCAGCACTGAGTA 2765 GATATCCTAAAAGGCAG ATGGTGATGAGGCCTGGTGATTCTG CCATGATCATGTTCACGCGCTGCATAACCTTTGCTA CATCACCA TCTGCCTTT 2766 AAAGGCAG A TGGTGATG 2767 Haemophilia BACTAATCGACCTTACCACTTTCACAATCTGCTAGCAAAGGTTA 2768 Ile(-40)PheTGCAGCGCGTGAACATG A TCATGGCAGAATCACCAGGCCTCA gATC-TTCTCACCATCTGCCTTTTAGGATATCTACTCAGTGCTGCAGCACTGAGTAGATATCCTAAAAGGCAGATGGTGATGAGGC 2769 CTGGTGATTCTGCCATGA TCATGTTCACGCGCTGCATAACCTT TGCTAGCAGATTGTGAAAGTGGTAAGGTCGATTAGT TGAACATG ATCATGGCA 2770 TGCCATGA T CATGTTCA 2771 Haemophilia BACTTTGGTACAACTAATCGACCTTACCACTTTCACAATCTGCT 2772 Arg(-44)HisAGCAAAGGTTATGCAGC G CGTGAACATGATCATGGCAGAATC CGC-CACACCAGGCCTCATCACCATCTGCCTTTTAGGATATCTAGATATCCTAAAAGGCAGATGGTGATGAGGCCTGGTGATTCT 2773 GCCATGATCATGTTCACG CGCTGCATAACCTTTGCTAGCAGA TTGTGAAAGTGGTAAGGTCGATTAGTTGTACCAAAGT TATGCAGC GCGTGAACA 2774 TGTTCACG C GCTGCATA 2775

EXAMPLE 15 Alpha Thalassemia—Hemoglobin Alpha Locus 1

[0136] The thalassemia syndromes are a heterogeneous group of inheritedanemias characterized by defects in the synthesis of one or more globinchain subunits. For example, beta-thalassemia discussed in Example 6, iscaused by a decrease in beta-chain production relative to alpha-chainproduction; the converse is the case for alpha-thalassemia. The attachedtable discloses the correcting oligonucleotide base sequences for thehemoglobin alpha locus 1 oligonucleotides of the invention. TABLE 22HBA1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ IDMutation Correcting Oligos NO: Thalassaemia alphaCCCTGGCGCGCTCGCGGCCCGGCACTCTTCTGGTCCCCACA 2776 Met(−1)ValGACTCAGAGAGAACCCACC A TGGTGCTGTCTCCTGCCGACA cATG-GTGAGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTTG 2777 TCGGCAGGAGACAGCACCA TGGTGGGTTCTCTCTGAGTCTGT GGGGACCAGAAGAGTGCCGGGCCGCGAGCGCGCCAGGG AACCCACC ATGGTGCTG 2778 CAGCACCA T GGTGGGTT 2779 Haemoglobin variantCACAGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCC 2780 Ala12AspGACAAGACCAACGTCAAGG C CGCCTGGGGTAAGGTCGGCGC GCC-GACGCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTGCACCTCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGC 2781 GCCGACCTTACCCCAGGCG GCCTTGACGTTGGTCTTGTCGG CAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGTG CGTCAAGG CCGCCTGGG 2782 CCCAGGCG G CCTTGACG 2783 Haemoglobin variantAGAGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAGACCA 2784 Gly15AspACGTCAAGGCCGCCTGGG G TAAGGTCGGCGCGCACGCTGG GGT-GATCGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCTAGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCGCC 2785 AGCGTGCGCGCCGACCTTAC CCCAGGCGGCCTTGACGTTGG TCTTGTCGGCAGGAGACAGCACCATGGTGGGTTCTCTCT CGCCTGGG GTAAGGTCG 2786 CGACCTTA C CCCAGGCG 2787 Haemoglobin variantCTGCCGACAAGACCAACGTCAAGGCCGCCTGGGGTAAGGTC 2788 Tyr24CysGGCGCGCACGCTGGCGAGT A TGGTGCGGAGGCCCTGGAGA TAT-TGTGGTGAGGCTCCCTCCCCTGCTCCGACCCGGGCTCCTCGCCGGCGAGGAGCCCGGGTCGGAGCAGGGGAGGGAGCCTCACC 2789 TCTCCAGGGCCTCCGCACCA TACTCGCCAGCGTGCGCGCCG ACCTTACCCCAGGCGGCCTTGACGTTGGTCTTGTCGGCAG TGGCGAGT ATGGTGCGG 2790 CCGCACCA T ACTCGCCA 2791 Haemogiobin variantGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCAC 2792 Glu27AspGCTGGCGAGTATGGTGCGGA G GCCCTGGAGAGGTGAGGCT GAGg-GATCCCTCCCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGAC CGGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGGGGAG 2793 GGAGCCTCACCTCTCCAGGGC CTCCGCACCATACTCGCCAG CGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTC GGTGCGGA GGCCCTGGA 2794 TCCAGGGC C TCCGCACC 2795 Haemoglobin variantGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG 2796 Asn68LysTGGCCGACGCGCTGACCAA C GCCGTGGCGCACGTGGACGA AACg-AAGCATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCGCGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG 2797 TCGTCCACGTGCGCCACGGC GTTGGTCAGCGCGTCGGCCAC CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC CTGACCAA CGCCGTGGC 2798 GCCACGGC G TTGGTCAG 2799 Haemoglobin variantAGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGACC 2800 Asp74GlyAACGCCGTGGCGCACGTGG A CGACATGCCCAACGCGCTGTC GAC-GGCCGCCCTGAGCGACCTGCACGCGCACAAGCTTCGGGTGGATCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGA 2801 CAGCGCGTTGGGCATGTCG TCCACGTGCGCCACGGCGTTGG TCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCT GCACGTGG ACGACATGC 2802 GCATGTCG T CCACGTGC 2803 Haemoglobin variantCAGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGAC 2804 Asp74HisCAACGCCGTGGCGCACGTG G ACGACATGCCCAACGCGCTGT gGAC-CACCCGCCCTGAGCGACCTGCACGCGCACAAGCTTCGGGTGGCCACCCGAAGCTTGTGCGCGTGCAGGTCGCTCAGGGCGGAC 2805 AGCGCGTTGGGCATGTCGT CCACGTGCGCCACGGCGTTGGT CAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTG CGCACGTG GACGACATG 2806 CATGTCGT C CACGTGCG 2807 Haemoglobin variantCACGGCAAGAAGGTGGCCGACGCGCTGACCAACGCCGTGG 2808 Asn78HisCGCACGTGGACGACATGCCC A ACGCGCTGTCCGCCCTGAGC cAAC-CACGACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACTAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGTCG 2809 CTCAGGGCGGACAGCGCGT TGGGCATGTCGTCCACGTGCGC CACGGCGTTGGTCAGCGCGTCGGCCACCTTCTTGCCGTG ACATGCCC AACGCGCTG 2810 CAGCGCGT T GGGCATGT 2811 Haemoglobin variantACCAACGCCGTGGCGCACGTGGACGACATGCCCAACGCGCT 2812 His87TyrGTCCGCCCTGAGCGACCTG C ACGCGCACAAGCTTCGGGTGG gCAC-TACACCCGGTCAACTTCAAGGTGAGCGGCGGGCCGGGAGCGATCGCTCCCGGCCCGCCGCTCACCTTGAAGTTGACCGGGTCC 2813 ACCCGAAGCTTGTGCGCGT GCAGGTCGCTCAGGGCGGACAG CGCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGGT GCGACCTG CACGCGCAC 2814 GTGCGCGT G CAGGTCGC 2815 Haemoglobin variantGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGA 2816 Lys90AsnGCGACCTGCACGCGCACAA G CTTCGGGTGGACCCGGTCAAC AAGc-AACTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAGCTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGT 2817 TGACCGGGTCCACCCGAAG CTTGTGCGCGTGCAGGTCGCTC AGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC 2818GCGCACAA G CTTCGGGT ACCCGAAG C TTGTGCGC 2819 Haemoglobin variantTGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTG 2820 Lys90ThrAGCGACCTGCACGCGCACA A GCTTCGGGTGGACCCGGTCAA AAG-ACGCTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGATCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGTT 2821 GACCGGGTCCACCCGAAGC TTGTGCGCGTGCAGGTCGCTCA GGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC CGCGCACA AGCTTCGGG 2822 CCCGAAGC T TGTGCGCG 2823 Haemoglobin variantACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGAGCGAC 2824 Arg92GlnCTGCACGCGCACAAGCTTC G GGTGGACCCGGTCAACTTCAA CGG-CAGGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTT 2825 GAAGTTGACCGGGTCCACC CGAAGCTTGTGCGCGTGCAGGT CGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTCCACGT CAAGCTTC GGGTGGACC 2826 GGTCCACC C GAAGCTTG 2827 Haemoglobin variantACGACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCAC 2828 Asp94GlyGCGCACAAGCTTCGGGTGG A CCCGGTCAACTTCAAGGTGAG GAC-GGCCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCT 2829 CACCTTGAAGTTGACCGGG TCCACCCGAAGCTTGTGCGCGT GCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGTCGT TCGGGTGG ACCCGGTCA 2830 TGACCGGG T CCACCCGA 2831 Haemoglobin variantACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG 2832 Pro95ArgCACAAGCTTCGGGTGGACC C GGTCAACTTCAAGGTGAGCGG CCG-CGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCGCGCGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCC 2833 GCTCACCTTGAAGTTGACC GGGTCCACCCGAAGCTTGTGCG CGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGT GGTGGACC CGGTCAACT 2834 AGTTGACC G GGTCCACC 2835 Haemoglobin variantCGGCGGCTGCGGGCCTGGGCCCTCGGCCCCACTGACCCTC 2836 Ser102ArgTTCTCTGCACAGCTCCTAAG C CACTGCCTGCTGGTGACCCTG AGCc-AGAGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCC 2837 AGGGTCACCAGCAGGCAGTG GCTTAGGAGCTGTGCAGAGAA GAGGGTCAGTGGGGCCGAGGGCCCAGGCCCGCAGCCGCCG CTCCTAAG CCACTGCCT 2838 AGGCAGTG G CTTAGGAG 2839 Haemoglobin variantTTCTCTGCACAGCTCCTAAGCCACTGCCTGCTGGTGACCCTG 2840 Glu116LysGCCGCCCACCTCCCCGCC G AGTTCACCCCTGCGGTGCACGC cGAG-AAGCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGCGCACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCG 2841 TGCACCGCAGGGGTGAACT CGGCGGGGAGGTGGGCGGCCA GGGTCACCAGCAGGCAGTGGCTTAGGAGCTGTGCAGAGAA TCCCCGCC GAGTTCACC 2842 GGTGAACT C GGCGGGGA 2843 Haemoglobin variantTCCTAAGCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTC 2844 Ala120GluCCCGCCGAGTTCACCCCTG C GGTGCACGCCTCCCTGGACAA GCG-GAGGTTCCTGGCTTCTGTGAGCACCGTGCTGACCTCCAAATATATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAGGAACTTG 2845 TCCAGGGAGGCGTGCACC GCAGGGGTGAACTCGGCGGGGA GGTGGGCGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGA CACCCCTG CGGTGCACG 2846 CGTGCACC G CAGGGGTG 2847 Thalassaemia alphaTGGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCAC 2848 Leu129ProGCCTCCCTGGACAAGTTCC T GGCTTCTGTGAGCACCGTGCTG CTG-CCGACCTCCAAATACCGTTAAGCTGGAGCCTCGGTGGCCATATGGCCACCGAGGCTCCAGCTTAACGGTATTTGGAGGTCAGC 2849 ACGGTGCTCACAGAAGCC AGGAACTTGTCCAGGGAGGCGTG CACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCA CAAGTTCC TGGCTTCTG 2850 CAGAAGCC A GGAACTTG 2851 Haemoglobin variantTGCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCG 2852 Arg141LeuTGCTGACCTCCAAATACC G TTAAGCTGGAGCCTCGGTGGCCA CGT-CTTTGCTTCTTGCCCCTTGGGCCTCCCCCCAGCCCCTCCTAGGAGGGGCTGGGGGGAGGCCCAAGGGGCAAGAAGCATGG 2853 CCACCGAGGCTCCAGCTTAA CGGTATTTGGAGGTCAGCACG GTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTGCA CAAATACC GTTAAGCTG 2854 CAGCTTAA C GGTATTTG 2855

EXAMPLE 16 Alphathalassemia—Hemoglobin Alpha Locus 2

[0137] The attached table discloses the correcting oligonucleotide basesequences for the hemoglobin alpha locus 2 oligonucleotides of theinvention. TABLE 23 HBA2 Mutations and Genome-Correcting Oligos ClinicalPhenotype & SEQ ID Mutation Correcting Oligos NO: Thalassaemia alphaCCTGGCGCGCTCGCGGGCCGGCACTCTTCTGGTCCCCACAG 2856 Met(−1)ThrACTCAGAGAGAACCCACCA T GGTGCTGTCTCCTGCCGACAAG ATG-ACGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCATGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTCTT 2857 GTCGGCAGGAGACAGCACC ATGGTGGGTTCTCTCTGAGTCT GTGGGGACCAGAAGAGTGCCGGCCCGCGAGCGCGCCAGG ACCCACCA TGGTGCTGT 2858 ACAGCACC A TGGTGGGT 2859 Haemoglobin variantCACAGACTCAGAGAGAACCCACCATGGTGCTGTCTCCTGCC 2860 Ala12AspGACAAGACCAACGTCAAGG C CGCCTGGGGTAAGGTCGGCGC GCC-GACGCACGCTGGCGAGTATGGTGCGGAGGCCCTGGAGAGGTGCACCTCTCCAGGGCCTCCGCACCATACTCGCCAGCGTGCGC 2861 GCCGACCTTACCCCAGGCG GCCTTGACGTTGGTCTTGTCGG CAGGAGACAGCACCATGGTGGGTTCTCTCTGAGTCTGTG CGTCAAGG CCGCCTGGG 2862 CCCAGGCG G CCTTGACG 2863 Haemoglobin variantAGAGAACCCACCATGGTGCTGTCTCCTGCCGACAAGACCAAC 2864 Lys16GluGTCAAGGCCGCCTGGGGT A AGGTCGGCGCGCACGCTGGCG tAAG-GAGAGTATGGTGCGGAGGCCCTGGAGAGGTGAGGCTCCCTCCGGAGGGAGCCTCACCTCTCCAGGGCCTCCGCACCATACTCG 2865 CCAGCGTGCGCGCCGACCT TACCCCAGGCGGCCTTGACGTT GGTCTTGTCGGCAGGAGACAGCACCATGGTGGGTTCTCT CCTGGGGT AAGGTCGGC 2866 GCCGACCT T ACCCCAGG 2867 Haemoglobin variantGGTGCTGTCTCCTGCCGACAAGACCAACGTCAAGGCCGCCT 2868 His20GlnGGGGTAAGGTCGGCGCGCA C GCTGGCGAGTATGGTGCGGA CACg-CAAGGCCCTGGAGAGGTGAGGCTCCCTCCCCTGCTCCGACCCGCGGGTCGGAGCAGGGGAGGGAGCCTCACCTCTCCAGGGCC 2869 TCCGCACCATACTCGCCAGC GTGCGCGCCGACCTTACCCCA GGCGGCCTTGACGTTGGTCTTGTCGGCAGGAGACAGCACC GGCGCGCA CGCTGGCGA 2870 TCGCCAGC G TGCGCGCC 2871 Haemoglobin variantGACCAACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCAC 2872 Glu27AspGCTGGCGAGTATGGTGCGGA G GCCCTGGAGAGGTGAGGCT GAGg-GACCCCTCCCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGAC CGGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGGGGAG 2873 GGAGCCTCACCTCTCCAGGGC CTCCGCACCATACTCGCCAG CGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGTTGGTC GGTGCGGA GGCCCTGGA 2874 TCCAGGGC C TCCGCACC Thalassaemia alphaACGTCAAGGCCGCCTGGGGTAAGGTCGGCGCGCACGCTGG 2876 Leu29ProCGAGTATGGTGCGGAGGCCC T GGAGAGGTGAGGCTCCCTCC CTG-CCGCCTGCTCCGACCCGGGCTCCTCGCCCGCCCGGACCCACAGCTGTGGGTCCGGGCGGGCGAGGAGCCCGGGTCGGAGCAGG 2877 GGAGGGAGCCTCACCTCTCC AGGGCCTCCGCACCATACTCG CCAGCGTGCGCGCCGACCTTACCCCAGGCGGCCTTGACGT GGAGGCCC TGGAGAGGT 2878 ACCTCTCC A GGGCCTCC 2879 Haemoglobin variantGCTTCTCCCCGCAGGATGTTCCTGTCCTTCCCCACCACCAAG 2880 Asp47HisACCTACTTCCCGCACTTC G ACCTGAGCCACGGCTCTGCCCA cGAC-CACGGTTAAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGATCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAACCTGG 2881 GCAGAGCCGTGGCTCAGGT CGAAGTGCGGGAAGTAGGTCTT GGTGGTGGGGAAGGACAGGAACATCCTGCGGGGAGAAGC CGCACTTC GACCTGAGC 2882 GCTCAGGT C GAAGTGCG 2883 Haemoglobin variantCTCCCCGCAGGATGTTCCTGTCCTTCCCCACCACCAAGACCT 2884 Leu48ArgACTTCCCGCACTTCGACC T GAGCCACGGCTCTGCCCAGGTTA CTG-CGGAGGGCCACGGCAAGAAGGTGGCCGACGCGCTGACCAATTGGTCAGCGCGTCGGCCACCTTCTTGCCGTGGCCCTTAAC 2885 CTGGGCAGAGCCGTGGCTC AGGTCGAAGTGCGGGAAGTAG GTCTTGGTGGTGGGGAAGGACAGGAACATCCTGCGGGGAG CTTCGACC TGAGCCACG 2886 CGTGGCTC A GGTCGAAG 2887 Haemoglobin variantCTGTCCTTCCCCACCACCAAGACCTACTTCCCGCACTTCGAC 2888 Gln54GIuCTGAGCCACGGCTCTGCC C AGGTTAAGGGCCACGGCAAGAA cCAG-GAGGGTGGCCGACGCGCTGACCAACGCCGTGGCGCACGTGGCCACGTGCGCCACGGCGTTGGTCAGCGCGTCGGCCACCTTC 2889 TTGCCGTGGCCCTTAACCT GGGCAGAGCCGTGGCTCAGGTC GAAGTGCGGGAAGTAGGTCTTGGTGGTGGGGAAGGACAG GCTCTGCC CAGGTTAAG 2890 CTTAACCT G GGCAGAGC 2891 Haemoglobin variantCCAAGACCTACTTCCCGCACTTCGACCTGAGCCACGGCTCTG 2892 Gly59AspCCCAGGTTAAGGGCCACG G CAAGAAGGTGGCCGACGCGCT GGC-GACGACCAACGCCGTGGCGCACGTGGACGACATGCCCAACGCGCGTTGGGCATGTCGTCCACGTGCGCCACGGCGTTGGTCAG 2893 CGCGTCGGCCACCTTCTTG CCGTGGCCCTTAACCTGGGCAG AGCCGTGGCTCAGGTCGAAGTGCGGGAAGTAGGTCTTGG GGGCCACG GCAAGAAGG 2894 CCTTCTTG C CGTGGCCC 2895 Haemoglobin variantGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG 2896 Asn68LysTGGCCGACGCGCTGACCAA C GCCGTGGCGCACGTGGACGA AACg-AAGCATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCGCGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG 2897 TCGTCCACGTGCGCCACGGC GTTGGTCAGCGCGTCGGCCAC CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC CTGACCAA CGCCGTGGC 2898 GCCACGGC G TTGGTCAG 2899 Haemoglobin variantGAGCCACGGCTCTGCCCAGGTTAAGGGCCACGGCAAGAAGG 2900 Asn68LysTGGCCGACGCGCTGACCAA C GCCGTGGCGCACGTGGACGA AACg-AAACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCGCGCGTGCAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATG 2901 TCGTCCACGTGCGCCACGGC GTTGGTCAGCGCGTCGGCCAC CTTCTTGCCGTGGCCCTTAACCTGGGCAGAGCCGTGGCTC CTGACCAA CGCCGTGGC 2902 GCCACGGC G TTGGTCAG 2903 Haemoglobin variantCGGCAAGAAGGTGGCCGACGCGCTGACCAACGCCGTGGCG 2904 Asn78LysCACGTGGACGACATGCCCAA C GCGCTGTCCGCCCTGAGCGA AACg-AAACCTGCACGCGCACAAGCTTCGGGTGGACCCGGTCAACTTCGAAGTTGACCGGGTCCACCCGAAGCTTGTGCGCGTGCAGGT 2905 CGCTCAGGGCGGACAGCGC GTTGGGCATGTCGTCCACGTGC GCCACGGCGTTGGTCAGCGCGTCGGCCACCTTCTTGCCG ATGCCCAA CGCGCTGTC 2906 GACAGCGC G TTGGGCAT 2907 Haemoglobin variantCGCTGACCAACGCCGTGGCGCACGTGGACGACATGCCCAAC 2908 Asp85ValGCGCTGTCCGCCCTGAGCG A CCTGCACGCGCACAAGCTTCG GAC-GTCGGTGGACCCGGTCAACTTCAAGGTGAGCGGCGGGCCGGGCCCGGCCCGCCGCTCACCTTGAAGTTGACCGGGTCCACCCG 2909 AAGCTTGTGCGCGTGCAGG TCGCTCAGGGCGGACAGCGCGT TGGGCATGTCGTCCACGTGCGCCACGGCGTTGGTCAGCG CCTGAGCG ACCTGCACG 2910 CGTGCAGG T CGCTCAGG 2911 Haemoglobin variantGGCGCACGTGGACGACATGCCCAACGCGCTGTCCGCCCTGA 2912 Lys90AsnGCGACCTGCACGCGCACAA G CTTCGGGTGGACCCGGTCAAC AAGc-AATTTCAAGGTGAGCGGCGGGCCGGGAGCGATCTGGGTCGAGCTCGACCCAGATCGCTCCCGGCCCGCCGCTCACCTTGAAGT 2913 TGACCGGGTCCACCCGAAG CTTGTGCGCGTGCAGGTCGCTC AGGGCGGACAGCGCGTTGGGCATGTCGTCCACGTGCGCC GCGCACAA GCTTCGGGT 2914 ACCCGAAG C TTGTGCGC 2915 Haemoglobin variantGACGACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCA 2916 Asp94HisCGCGCACAAGCTTCGGGTG G ACCCGGTCAACTTCAAGGTGA gGAC-CACGCGGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCCGCTC 2917 ACCTTGAAGTTGACCGGGT CCACCCGAAGCTTGTGCGCGTG CAGGTCGCTCAGGGCGGACAGCGCGTTGGGCATGTCGTC TTCGGGTG GACCCGGTC 2918 GACCGGGT C CACCCGAA 12919 Haemoglobin variantACATGCCCAACGCGCTGTCCGCCCTGAGCGACCTGCACGCG 2920 Pro95LeuCACAAGCTTCGGGTGGACC C GGTCAACTTCAAGGTGAGCGG CCG-CTGCGGGCCGGGAGCGATCTGGGTCGAGGGGCGAGATGGCGCGCGCCATCTCGCCCCTCGACCCAGATCGCTCCCGGCCCGCC 2921 GCTCACCTTGAAGTTGACC GGGTCCAGCCGAAGCTTGTGCG CGTGCAGGTGGCTCAGGGCGGACAGCGCGTTGGGCATGT GGTGGACC CGGTCAACT 2922 AGTTGACC G GGTCCACC 2923 Haemoglobin variantTAGCGCAGGCGGCGGCTGCGGGCCTGGGCCGCACTGACCC 2924 Ser102ArgTCTTCTCTGCACAGCTCCTA A GCCACTGCCTGCTGGTGACCC aAGC-CGCTGGCCGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGCGGCCAG 2925 GGTCACCAGCAGGCAGTGGC TTAGGAGCTGTGCAGAGAAGA GGGTCAGTGCGGCCCAGGCCCGCAGCCGCCGCCTGCGCTA AGCTCCTA AGCCACTGC 2926 GCAGTGGC T TAGGAGCT 2927 Haemoglobin H diseaseGGCGGCGGCTGCGGGCCTGGGCCGCACTGACCCTCTTCTCT 2928 Cys104TyrGCACAGCTCCTAAGCCACT G CCTGCTGGTGACCCTGGCCGC TGC-TACCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGCCTCGAGGCGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGG 2929 CGGCCAGGGTCACCAGCAGG CAGTGGCTTAGGAGCTGTGCA GAGAAGAGGGTCAGTGCGGCCCAGGCCCGCAGCCGCCGCC AAGCCACT GCCTGCTGG 2930 CCAGCAGG C AGTGGCTT 2931 Haemoglobin variantCCGCACTGACCCTCTTCTCTGCACAGCTCCTAAGCCACTGCC 2932 Ala111ValTGCTGGTGACCCTGGCCG C CCACCTCCCCGCCGAGTTCACC GCC-GTCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTGGCTTCGAAGCCAGGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGT 2933 GAACTCGGCGGGGAGGTGG GCGGCCAGGGTCACCAGCAGG CAGTGGCTTAGGAGCTGTGCAGAGAAGAGGGTCAGTGCGG CCTGGCCG CCCACCTCC 2934 GGAGGTGG G CGGCCAGG 2935 Haemoglobin variantTCCTAAGCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTC 2936 Ala120GluCCCGCCGAGTTCACCCCTG C GGTGCACGCCTCCCTGGACAA GCG-GAGGTTCCTGGCTTCTGTGAGCACCGTGCTGACCTCCAAATATATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAGGAACTTG 2937 TCCAGGGAGGCGTGCACC GCAGGGGTGAACTCGGCGGGGA GGTGGGCGGCCAGGGTCACCAGCAGGCAGTGGCTTAGGA CACCCCTG CGGTGCACG 2938 CGTGCACC G CAGGGGTG 2939 Haemoglobin variantCCACTGCCTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCG 2940 His122GlnAGTTCACCCCTGCGGTGCA C GCCTCCCTGGACAAGTTCCTG CACg-CAGGCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAATTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCAG 2941 GAACTTGTCCAGGGAGGC GTGCACCGCAGGGGTGAACTCGG CGGGGAGGTGGGCGGCCAGGGTCACCAGCAGGCAGTGG GCGGTGCA CGCCTCCCT 2942 AGGGAGGC G TGCACCGC 2943 Haemoglobin variantCACTGCCTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGA 2944 Ala123SerGTTCACCCCTGCGGTGCAC G CCTCCCTGGACAAGTTCCTGG cGCC-TCCCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAAGCTTAACGGTATTTGGAGGTCAGCACGGTGCTCACAGAAGCCA 2945 GGAACTTGTCCAGGGAGG CGTGCACCGCAGGGGTGAACTCG GCGGGGAGGTGGGCGGCCAGGGTCACCAGCAGGCAGTG CGGTGCAC GCCTCCCTG 2946 CAGGGAGG C GTGCACCG 2947 Thalassaemia alphaTGCTGGTGACCCTGGCCGCCCACCTCCCCGCCGAGTTCACC 2948 Leu125ProCCTGCGGTGCACGCCTCCC T GGACAAGTTCCTGGCTTCTGT CTG-CCGGAGCACCGTGCTGACCTCCAAATACCGTTAAGCTGGAGCGCTCCAGCTTAACGGTATTTGGAGGTCAGCACGGTGCTCACA 2949 GAAGCCAGGAACTTGTCC AGGGAGGCGTGCACCGCAGGGG TGAACTCGGCGGGGAGGTGGGCGGCCAGGGTCACCAGCA CGCCTCCC TGGACAAGT 2950 ACTTGTCC A GGGAGGCG 2951 Haemoglobin variantGCCCACCTCCCCGCCGAGTTCACCCCTGCGGTGCACGCCTC 2952 Ser131ProCCTGGACAAGTTCCTGGCT T CTGTGAGCACCGTGCTGACCTC tTCT-CCTCAAATACCGTTAAGCTGGAGCCTCGGTAGCCGTTCCTCGAGGAACGGCTACCGAGGCTCCAGCTTAACGGTATTTGGAG 2953 GTCAGCACGGTGCTCACAG AAGCCAGGAACTTGTCCAGGGA GGCGTGCACCGCAGGGGTGAACTCGGCGGGGAGGTGGGC TCCTGGCT TCTGTGAGC 2954 GCTCACAG A AGCCAGGA 2955 Haemoglobin variantGAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCT 2956 Leu136MetGGCTTCTGTGAGCACCGTGCTGACCTCCAAATACCGTTAAGC gCTG-ATGTGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTAGGCCCAGCGGGCAGGAGGAACGGCTACCGAGGCTCCAGC 2957 TTAACGGTATTTGGAGGTCA GCACGGTGCTCACAGAAGCCAG GAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACTC GCACCGTG CTGACCTCC 2958 GGAGGTCA G CACGGTGC 2959 Haemoglobin variantAGTTCACCCCTGCGGTGCACGCCTCCCTGGACAAGTTCCTG 2960 Leu136ProGCTTCTGTGAGCACCGTGC T GACCTCCAAATACCGTTAAGCT CTG-CCGGGAGCCTCGGTAGCCGTTCCTCCTGCCCGCTGGGCCTCGAGGCCCAGCGGGCAGGAGGAACGGCTACCGAGGCTCCAG 2961 CTTAACGGTATTTGGAGGTC AGCACGGTGCTCACAGAAGCCA GGAACTTGTCCAGGGAGGCGTGCACCGCAGGGGTGAACT CACCGTGC TGACCTCCA 2962 TGGAGGTC A GCACGGTG 2963 Haemoglobin variantGTGCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACC 2964 Arg141CysGTGCTGACCTCCAAATAC C GTTAAGCTGGAGCCTCGGTAGCC cCGT-TGTGTTCCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAACGGC 2965 TACCGAGGCTCCAGCTTAAC GGTATTTGGAGGTCAGCACGGT GCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTGCAC CCAAATAC CGTTAAGCT 2966 AGCTTAAC G GTATTTGG 2967 Haemogtobin variantCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTG 2968 Term142GlnCTGACCTCCAAATACCGT T AAGCTGGAGCCTCGGTAGCCGTT tTAA-CAACCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCGGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAAC 2969 GGCTACCGAGGCTCCAGCTT AACGGTATTTGGAGGTCAGCA CGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG AATACCGT TAAGCTGGA 2970 TCCAGCTT A ACGGTATT 2971 Haemoglobin variantCACGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTG 2972 Thrm142LysCTGACCTCCAAATACCGT T AAGCTGGAGCCTCGGTAGCCGTT tTAA-AAACCTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCGGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGGAAC 2973 GGCTACCGAGGCTCCAGCTT AACGGTATTTGGAGGTCAGCA CGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCGTG AATACCGT TAAGCTGGA 2974 TCCAGCTT A ACGGTATT 2975 Haemoglobin variantCGCCTCCCTGGACAAGTTCCTGGCTTCTGTGAGCACCGTGCT 2976 Term142TyrGACCTCCAAATACCGTTA A GCTGGAGCCTCGGTAGCCGTTCC TAAg-TATTCCTGCCCGCTGGGCCTCCCAACGGGCCCTCCTCCCCGGGGAGGAGGGCCCGTTGGGAGGCCCAGCGGGCAGGAGG 2977 AACGGCTACCGAGGCTCCAGC TTAACGGTATTTGGAGGTCAG CACGGTGCTCACAGAAGCCAGGAACTTGTCCAGGGAGGCG TACCGTTA AGCTGGAGC 2978 GCTCCAGC T TAACGGTA 2979

EXAMPLE 17 Human Mismatch Repair—MLH1

[0138] The human MLH1 gene is homologous to the bacterial mutL gene,which is involved in mismatch repair. Mutations in the MLH1 gene havebeen identified in many individuals with hereditary nonpolyposiscolorectal cancer (HNPCC). Mutations in the MLH1 gene are alsoimplicated in predispositon to a variety of cancers associated with, forexample, Muir-Torre syndrome and Turcot syndrome. The attached tablediscloses the correcting oligonucleotide base sequences for the MLH1oligonucleotides of the invention. TABLE 24 MLH1 Mutations andGenome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation CorrectingOligos NO: Non-polyposis TTGGCTGAAGGCACTTCCGTTGAGCATCTAGACGTTTCCTTG 2980colorectal cancer GCTCTTCTGGCGCCAAAA T GTCGTTCGTGGCAGGGGTTATTC Met1ArgGGCGGCTGGACGAGACAGTGGTGAACCGCATCGCGGC ATG-AGGGCCGCGATGCGGTTCACCACTGTCTCGTCCAGCCGCCGAAT 2981 AACCCCTGCCACGAACGAC ATTTTGGCGCCAGAAGAGCCAA GGAAACGTCTAGATGCTCAACGGAAGTGCCTTCAGCCAA CGCCAAAA TGTCGTTCG 2982 CGAACGAC A TTTTGGCG 2983 Non-polyposisTTGGCTGAAGGCACTTCCGTTGAGCATCTAGACGTTTCCTTG 2984 colorectal cancerGCTCTTCTGGCGCCAAAA T GTCGTTCGTGGCAGGGGTTATTC Met1LysGGCCGCTGGACGAGACAGTGGTGAACCGCATCGCGGC ATG-AAGGCCGCGATGCGGTTCACCACTGTCTCGTCCAGCCGCCGAAT 2985 AACCCCTGCCACGAACGAC ATTTTGGCGCCAGAAGAGCCAA GGAAACGTCTAGATGCTCAACGGAAGTGCCTTCAGCCAA CGCCAAAA TGTCGTTCG 2986 CGAACGAC A TTTTGGCG 2987 Non-polyposisTGGTGAACCGCATCGCGGCGGGGGAAGTTATCCAGCGGCCA 2988 colorectal cancerGCTAATGCTATCAAAGAGA T GATTGAGAACTGGTACGGAGGG Met35ArgAGTCGAGCCGGGCTCACTTAAGGGCTACGACTTAACGG ATG-AGGCCGTTAAGTCGTAGCCCTTAAGTGAGCCCGGCTCGACTCCCT 2989 CCGTACCAGTTCTCAATC ATCTCTTTGATAGCATTAGCTGGCC GCTGGATAACTTCCCCCGCCGCGATGCGGTTCACCA CAAAGAGA TGATTGAGA 2990 TCTCAATC A TCTCTTTG 2991 Non-polyposisTAGAGTAGTTGCAGACTGATAAATTATTTTCTGTTTGATTTGCC 2992 colorectal cancerAGTTTAGATGCAAAAT C CACAAGTATTCAAGTGATTGTTAAAG Ser44PheAGGGAGGCCTGAAGTTGATTCAGATCCAAGACAA TCC-TTCTTGTCTTGGATCTGAATCAACTTCAGGCCTCCCTCTTTAACAA 2993 TCACTTGAATACTTGTG GATTTTGCATCTAAACTGGCAAATCA AACAGAAAATAATTTATCAGTCTGCAACTACTCTA TGCAAAAT CCACAAGTA 2994 TACTTGTG G ATTTTGCA 2995 Non-polyposisGCAAAATCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGC 2996 colorectal cancerCTGAAGTTGATTCAGATC C AAGACAATGGCACCGGGATCAGG Gln62LysGTAAGTAAAACCTCAAAGTAGCAGGATGTTTGTGCGC CAA-AAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTACCCTGAT 2997 CCCGGTGCCATTGTCTT GGATCTGAATCAACTTCAGGCCTCC CTCTTTAACAATCACTTGAATACTTGTGGATTTTGC TTCAGATC CAAGACAAT 2998 ATTGTCTT G GATCTGAA 2999 Non-polyposisGCAAAATCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGC 3000 colorectal cancerCTGAAGTTGATTCAGATC C AAGACAATGGCACCGGGATCAGG Gln62TermGTAAGTAAAACCTCAAAGTAGCAGGATGTTTGTGCGC CAA-TAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTACCCTGAT 3001 CCCGGTGCCATTGTCTT GGATCTGAATCAACTTCAGGCCTCC CTCTTTAACAATCACTTGAATATTTGTGGATTTTGC TTCAGATC CAAGACAAT 3002 ATTGTCTT G GATCTGAA 3003 Non-polyposisCCACAAGTATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGT 3004 colorectal cancerTGATTCAGATCCAAGACA A TGGCACCGGGATCAGGGTAAGTA Asn64SerAAACCTCAAAGTAGCAGGATGTTTGTGCGCTTCATGG AAT-AGTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGTTTTACTTA 3005 CCCTGATCCCGGTGCCA TTGTCTTGGATCTGAATCAACTTCA GGCCTCCCTCTTTAACAATCACTTGAATACTTGTGG CCAAGACA ATGGCACCG 3006 CGGTGCCA T TGTCTTGG 3007 Non-polyposisATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA 3008 colorectal cancerTCCAAGACAATGGCACC G GGATCAGGGTAAGTAAAACCTCAA Gly67ArgAGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA GGG-AGGTGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT 3009 TTTACTTACCCTGATCC CGGTGCCATTGTCTTGGATCTGAATC AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT ATGGCACC GGGATCAGG 3010 CCTGATCC C GGTGCCAT 3011 Non-polyposisATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA 3012 colorectal cancerTCCAAGACAATGGCACC G GGATCAGGGTAAGTAAAACCTCAA Gly67ArgAGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA GGG-CGGTGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT 3013 TTTACTTACCCTGATCC CGGTGCCATTGTCTTGGATCTGAATC AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT ATGGCACC GGGATCAGG 3014 CGTGATCC C GGTGCCAT 3015 Non-polyposisATTCAAGTGATTGTTAAAGAGGGAGGCCTGAAGTTGATTCAGA 3016 colorectal cancerTCCAAGACAATGGCACC G GGATCAGGGTAAGTAAAACCTCAA Gly67TrpAGTAGCAGGATGTTTGTGCGCTTCATGGAAGAGTCA GGG-TGGTGACTCTTCCATGAAGCGCACAAACATCCTGCTACTTTGAGGT 3017 TTTACTTACCCTGATCC CGGTGCCATTGTCTTGGATCTGAATC AACTTCAGGCCTCCCTCTTTAACAATCACTTGAAT ATGGCACC GGGATCAGG 3018 GCTGATCC C GGTGCCAT 3019 Non-polyposisGTAACATGATTATTTACTCATCTTTTTGGTATCTAACAGAAAGA 3020 colorectal cancerAGATCTGGATATTGTA T GTGAAAGGTTCACTACTAGTAAACTG Cys77ArgCAGTCCTTTGAGGATTTAGCCAGTATTTCTACCT TGT-CGTAGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTTTACT 3021 AGTAGTGAACCTTTCAC ATACAATATCCAGATCTTCTTTCTGTT AGATACCAAAAAGATGAGTAAATAATCATGTTAC ATATTGTA TGTGAAAGG 3022 CCTTTCAC A TACAATAT 3023 Non-polyposisTAACATGATTATTTACTCATCTTTTTGGTATCTAACAGAAAGAA 3024 colorectal cancerGATCTGGATATTGTAT G TGAAAGGTTCACTACTAGTAAACTGC Cys77TyrAGTCCTTTGAGGATTTAGCCAGTATTTCTACCTA TGT-TATTAGGTAGAAATACTGGCTAAATCCTCAAAGGACTGCAGTTTAC 3025 TAGTAGTGAACCTTTCA CATACAATATCCAGATCTTCTTTCTGT TAGATACCAAAAAGATGAGTAAATAATCATGTTA TATTGTAT GTGAAAGGT 3026 ACCTTTCA C ATACAATA 3027 Non-polyposisTCTGGATATTGTATGTGAAAGGTTCACTACTAGTAAACTGCAGT 3028 colorectal cancerCCTTTGAGGATTTAGCC A GTATTTCTACCTATGGCTTTCGAGG Ser93GlyTGAGGTAAGCTAAAGATTCAAGAAAGTGTAAAAT AGT-GGTATTTTACACATTTCTTGAATCTTTAGCTTACCTCACCTCGAAAG 3029 CCATAGGTAGAAATAC TGGCTAAATCCTCAAAGGACTGCAGTT TACTAGTAGTGAACCTTTCACATACAATATCCAG ATTTAGCC AGTATTTCT 3030 AGAAATAC T GGCTAAAT 3031 Non-polyposisTTCACTACTAGTAAACTGCAGTCCTTTGAGGATTTAGCCAGTA 3032 colorectal cancerTTTCTACCTATGGCTTT C GAGGTGAGGTAAGCTAAAGATTCAA Arg101TermGAAATGTGTAAAATATCCTGCTGTGATGACATTGT CGA-TGAACAATGTCATCACAGGAGGATATTTTACACATTTCTTGAATCTT 3033 TAGCTTACCTCACCTC GAAAGCCATAGGTAGAAATACTGGCTA AATCCTCAAAGGACTGCAGTTTACTAGTAGTGAA ATGGCTTT CGAGGTGAG 3034 CTCACCTC G AAAGCCAT 3035 Non-polyposisACCCAGCAGTGAGTTTTTCTTTCAGTCTATTTTCTTTTCTTCCT 3036 colorectal cancerTAGGCTTTGGCCAGCA T AAGCCATGTGGCTCATGTTACTATTA Ile107ArgCAACGAAAACAGCTGATGGAAAGTGTGCATACAG ATA-AGACTGTATGCACACTTTCCATCAGCTGTTTTCGTTGTAATAGTAA 3037 CATGAGCCACATGGCTT ATGCTGGCCAAAGCCTAAGGAAGAA AAGAAAATAGACTGAAAGAAAAACTCACTGCTGGGT GGCCAGCA TAAGCCATG 3038 CATGGCTT A TGCTGGCC 3039 Non-polyposisTTTCTTTTCTTCCTTAGGCTTTGGCCAGCATAAGCCATGTGGC 3040 colorectal cancerTCATGTTACTATTACAA C GAAAACAGCTGATGGAAAGTGTGCA Thr117ArgTACAGGTATAGTGCTGACTTCTTTTACTCATATAT ACG-AGGATATATGAGTAAAAGAAGTCAGCACTATACCTGTATGCACACT 3041 TTCCATCAGCTGTTTTC GTTGTAATAGTAACATGAGCCACATG GCTTATGCTGGCCAAAGCCTAAGGAAGAAAAGAAA TATTACAA CGAAAACAG 3042 CTGTTTTC G TTGTAATA 3043 Non-polyposisTTTCTTTTCTTCCTTAGGCTTTGGCCAGCATAAGCCATGTGGC 3044 colorectal cancerTCATGTTACTATTACAA C GAAAAACAGCTGATGGAAAGTGTGCA Thr117MetTACAGGTATAGTGCTGACTTCTTTTACTCATATAT ACG-ATGATATATGAGTAAAAGAAGTCAGCACTATACCTGTATGCACACT 3045 TTCCATCAGCTGTTTTC GTTGTAATAGTAACATGAGCCACATG GCTTATGCTGGCCAAAGCCTAAGGAAGAAAAGAAA TATTACAA CGAAAACAG 3046 GTGTTTTC G TTGTAATA 3047 Non-polyposisTCTATCTCTCTACTGGATATTAATTTGTTATATTTTCTCATTAGA 3048 coIorectal cancerGCAAGTTACTCAGAT G GAAAACTGAAAGCCCCTCCTAAACCA Gly133TermTGTGCTGGCAATCAAGGGACCCAGATCACGGTAA GGA-TGATTACCGTGATCTGGGTCCCTTGATTGCCAGCACATGGTTTAG 3049 GAGGGGCTTTCAGTTTTC CATCTGAGTAACTTGCTCTAATGAG AAAATATAACAAATTAATATCCAGTAGAGAGATAGA ACTCAGAT GGAAAACTG 3050 CAGTTTTC C ATCTGAGT 3051 Non-polyposisTAGTGTGTGTTTTGGCAACTCTTTTCTTACTCTTTTGTTTTTC 3052 colorectal cancerTTTTCCAGGTATTCAG T ACACAATGCAGGCATTAGTTTCTCAG Val185GlyTTAAAAAAGTAAGTTCTTGGTTTATGGGGGATGG GTA-GGACCATCCCCCATAAACCAAGAACTTACTTTTTTAACTGAGAAAC 3053 TAATGCCTGCATTGTGT ACTGAATACCTGGAAAAGAAAACAA AAGAGTAAGAAAAGAGTTGCCAAAAACACACACTA GTATTCAG TACACAATG 3054 CATTGTGT A CTGAATAC 3055 Non-polyposisTTTCTTACTCTTTTGTTTTTCTTTTCCAGGTATTCAGTACACAAT 3056 colorectal cancerGCAGGCATTAGTTTC T CAGTTAAAAAAGTAAGTTCTTGGTTTAT Ser193ProGGGGGATGGTTTTGTTTTATGAAAAGAAAAAA TCA-CCATTTTTTCTTTTCATAAAACAAAACCATCCCCCATAAACCAAGAA 3057 CTTACTTTTTTAACTG AGAAACTAATGCCTGCATTGTGTACTG AATACCTGGAAAAGAAAAACAAAAGAGTAAGAAA TTAGTTTC TCAGTTAAA 3058 TTTAACTG A GAAACTAA 3059 Non-polyposisTTTGTTTATCAGCAAGGAGAGACAGTAGCTGATGTTAGGACA 3060 colorectal cancerCTACCCAATGCCTCAACC G TGGACAATATTCGCTCCATCTTTG Val213MetGAAATGCTGTTAGTGGGTATGTCGATAACCTATATA GTG-ATGTATATAGGTTATCGACATACCGACTAACAGCATTTCCAAAGAT 3061 GGAGCGAATATTGTCCA CGGTTGAGGCATTGGGTAGTGTCCT AACATCAGCTACTGTCTCTCCTTGCTGATAAACAAA CCTCAACC GTGGACAAT 3062 ATTGTCCA C GGTTGAGG 3063 Non-polyposisCAAGGAGAGACAGTAGCTGATGTTAGGACACTACCCAATGCC 3064 colorectal cancerTCAACCGTGGACAATATT C GCTCCATCTTTGGAAATGCTGTTA Arg217CysGTCGGTATGTCGATAACCTATATAAAAAAATCTTTT CGC-TGCAAAAGATTTTTTATATAGGTTATCGACATACCGACTAACAGCA 3065 TTTCCAAAGATGGAGC GAATATTGTCCACGGTTGAGGCATTG GGTAGTGTCCTAACATCAGCTACTGTCTCTCCTTG ACAATATT CGCTCCATC 3066 GATGGAGC G AATATTGT 3067 Non-polyposisGAGACAGTAGCTGATGTTAGGACACTACCCAATGCCTCAACC 3068 colorectal cancerGTGGACAATATTCGCTCC A TCTTTGGAAATGCTGTTAGTCGGT Ile219ValATGTCGATAACCTATATAAAAAAATCTTTTACATTT ATC-GTCAAATGTAAAAGATTTTTTTATATAGGTTATCGACATACCGACTA 3069 ACAGCATTTCCAAAGA TGGAGAGCGAATATTGTCCACGGTTGAG GCATTGGGTAGTGTCCTAACATCAGCTACTGTCTC TTCGCTCCA TCTTTGGA 3070 TCCAAAGA T GGAGCGAA 3071 Non-polyposisCTAATAGAGAACTGATAGAAATTGGATGTGAGGATAAAACCCT 3072 colorectal cancerAGCCTTCAAAATGAATG G TTACATATCCAATGCAAACTACTCA Gly244AspGTGAAGAAGTGCATCTTCTTACTCTTCATCAACCG GGT-GATCGGTTGATGAAGAGTAAGAAGATGCACTTCTTCACTGAGTAG 3073 TTTGCATTGGATATGTAA CCATTCATTTTGAAGGCTAGGGTTT TATCCTCACATCCAATTTCTATCAGTTCTCTATTAG AATGAATG GTTACATAT 3074 ATATGTAA C CATTCATT 3075 Non-polyposisGATGTGAGGATAAAACCCTAGCCTTCAAAATGAATGGTTACAT 3076 colorectal cancerATCCAATGCAAACTACT C AGTGAAGAAGTGCATCTTCTTACTC Ser252TermTTCATCAACCGTAAGTTAAAAAGAACCACATGGGA TCA-TAATCCCATGTGGTTCTTTTTAACTTACGGTTGATGAAGAGTAAGA 3077 AGATGGACTTCTTCACT GAGTAGTTTGCATTGGATATGTAACC ATTCATTTTGAAGGCTAGGGTTTTATCCTCACATC AAACTACT CAGTGAAGA 3078 TCTTCACT G AGTAGTTT 3079 Non-polyposisCACCCCTCAGGACAGTTTTGAACTGGTTGCTTTCTTTTTATTG 3080 colorectal cancerTTTAGATCGTCTGGTAG A ATCAACTTCCTTGAGAAAAGCCATA Glu268GlyGAAACAGTGTATGCAGCCTATTTGCCCAAAAACAC GAA-GGAGTGTTTTTGGGCAAATAGGCTGCATACACTGTTTCTATGGCTT 3081 TTCTCAAGGAAGTTGAT TCTACCAGACGATCTAAACAATAAAA AGAAAGCAACCAGTTCAAAACTGTCCTGAGGGGTG TCTGGTAG AATCAACTT 3082 AAGTTGAT T CTACCAGA 3083 Non-polyposisCCCTCAGGACAGTTTTGAACTGGTTGCTTTCTTTTTATTGTTTA 3084 colorectal cancerGATCGTCTGGTAGAAT C AACTTCCTTGAGAAAAGCCATAGAAA Ser269TermCAGTGTATGCAGCCTATTTGCCCAAAAACACACA TCA-TGATGTGTGTTTTTGGGCAAATAGGCTGCATACACTGTTTCTATGG 3085 CTTTTCTCAAGGAAGTT GATTCTACCAGACGATCTAAACAATA AAAAGAAAGCAACCAGTTCAAAACTGTCCTGAGGG GGTAGAAT CAACTTCCT 3086 AGGAAGTT G ATTCTACC 3087 Non-polyposisCTTTTTCTCCCCCTCCCACTATCTAAGGTAATTGTTCTCTCTTA 3088 colorectal cancerTTTTCCTGACAGTTTA G AAATCAGTCCCCAGAATGTGGATGTT Glu297TermAATGTGCACCCCACAAAGCATGAAGTTCACTTCC GAA-TAAGGAAGTGAACTTCATGCTTTGTGGGGTGCACATTAACATCCA 3089 CATTCTGGGGACTGATTT CTAAACTGTCAGGAAAATAAGAGAG AACAATTACCTTAGATAGTGGGAGGGGGAGAAAAAG ACAGTTTA GAAATCAGT 3090 ACTGATTT C TAAACTGT 3091 Non-polyposisCTCCCACTATCTAAGGTAATTGTTCTCTCTTATTTTCCTGACAG 3092 colorectal cancerTTTAGAAATCAGTCCC C AGAATGTGGATGTTAATGTGCACCCC Gln30TTermACAAAGCATGAAGTTCACTTCCTGCACGAGGAGA CAG-TAGTCTCCTCGTGCAGGAAGTGAACTTCATGCTTTGTGGGGTGCA 3093 CATTAACATCCACATTCT GGGGACTGATTTCTAAACTGTCAGG AAAATAAGAGAGAACAATTACCTTAGATAGTGGGAG TCAGTCCC CAGAATGTG 3094 CACATTCT G GGGACTGA 3095 Non-polyposisATGTGCACCCCACAAAGCATGAAGTTCACTTCCTGCACGAGG 3096 colorectal cancerAGAGCATCCTGGAGCGGG T GCAGCAGCACATCGAGAGCAAG Val326AlaCTCCTGGGCTCCAATTCCTCCAGGATGTACTTCACCCA GTG-GCGTGGGTGAAGTACATCCTGGAGGAATTGGAGCCCAGGAGCTT 3097 GCTCTCGATGTGCTGCTGC ACCCGCTCCAGGATGCTCTCCT CGTGCAGGAAGTGAACTTCATGCTTTGTGGGGTGCACAT GGAGCGGG TGCAGCAGC 3098 GCTGCTGC A CCCGCTCC 3099 Non-polyposisCCACAAAGCATGAAGTTCACTTCCTGCACGAGGAGAGCATCC 3100 colorectal cancerTGGAGCGGGTGCAGCAGC A CATCGAGAGCAAGCTCCTGGGC His329ProTCCAATTCCTCCAGGATGTACTTCACCCAGGTCAGGGC CAC-CCCGCCCTGACCTGGGTGAAGTACATCCTGGAGGAATTGGAGCC 3101 CAGGAGCTTGCTCTCGATG TGCTGCTGCACCCGCTCCAGGA TGCTCTCCTCGTGCAGGAAGTGAACTTCATGCTTTGTGG GCAGCAGC ACATCGAGA 3102 TCTCGATG T GCTGCTGC 3103 Non-polyposisCAAGTCTGACCTCGTCTTCTACTTCTGGAAGTAGTGATAAGGT 3104 colorectal cancerCTATGCCCACCAGATGG T TCGTACAGATTCCCGGGAACAGAA Val384AspGCTTGATGCATTTCTGCAGCCTCTGAGCAAACCCCT GTT-GATAGGGGTTTGCTCAGAGGCTGCAGAAATGCATCAAGCTTCTGT 3105 TCCCGGGAATCTGTACGA ACCATCTGGTGGGCATAGACCTTA TCACTACTTCCAGAAGTAGAAGACGAGGTCAGACTTG CCAGATGG TTCGTACAG 3106 CTGTACGA A CCATCTGG 3107 Non-polyposisAGTGGCAGGGCTAGGCAGCAAGATGAGGAGATGCTTGAACT 3108 colorectal cancerCCCAGCCCCTGCTGAAGTG G CTGCCAAAAATCAGAGCTTGGA Ala44TThrGGGGGATACAACAAAGGGGACTTCAGAAATGTCAGAGA GCT-ACTTCTCTGACATTTCTGAAGTCCCCTTTGTTGTATCCCCCTCCAA 3109 GCTCTGATTTTTGGCAG CCACTTCAGCAGGGGCTGGGAGTTC AAGCATCTCCTCATCTTGCTGCCTAGCCCTGCCACT CTGAAGTG GCTGCCAAA 3110 TTTGGCAG C CACTTCAG 3111 Non-polyposisCTTCATTGCAGAAAGAGACATCGGGAAGATTCTGATGTGGAA 3112 colorectal cancerATGGTGGAAGATGATTCC C GAAAGGAAATGACTGCAGCTTGT Arg487TermACCCCCCGGAGAAGGATCATTAACCTCACTAGTGTTT CGA-TGAAAACACTAGTGAGGTTAATGATCCTTCTCCGGGGGGTACAAG 3113 CTGCAGTCATTTCCTTTC GGGAATCATCTTCCACCATTTCCAC ATCAGAATCTTCCCGATGTCTCTTTCTGCAATGAAG ATGATTCC CGAAAGGAA 3114 TTCCTTTC G GGAATCAT 3115 Non-polyposisAGACATCGGGAAGATTCTGATGTGGAAATGGTGGAAGATGAT 3116 colorectal cancerTCCCGAAAGGAAATGACT G CAGCTTGTACCCCCCGGAGAAG Ala492ThrGATCATTAACCTCACTAGTGTTTTGAGTCTCCAGGAAG GCA-ACACTTCCTGGAGACTCAAAACACTAGTGAGGTTAATGATCCTTCT 3117 CCGGGGGGTACAAGCTG CAGTCATTTCCTTTCGGGAATCATC TTCCACCATTTCCACATCAGAATCTTCCCGATGTCT AAATGACT GCAGCTTGT 3118 ACAAGCTG C AGTCATTT 3119 Non-polyposisCCCGAAAGGAAATGACTGCAGCTTGTACCCCCCGGAGAAGG 3120 colorectal cancerATCATTAACCTCACTAGTG T TTTGAGTCTCCAGGAAGAAATTA Val506AlaATGAGCAGGGACATGAGGGTACGTAAACGCTGTGGCC GTT-GCTGGCCACAGCGTTTACGTACCCTCATGTCCCTGCTCATTAATTT 3121 CTTCCTGGAGACTCAAA ACACTAGTGAGGTTAATGATCCTTCT CCGGGGGGTACAAGCTGCAGTCATTTGCTTTCGGG CACTAGTG TTTTGAGTC 3122 GACTCAAA A CACTAGTG 3123 Non-polyposisGGGAGATGTTGCATAACCACTCCTTCGTGGGCTGTGTGAATC 3124 colorectal cancerCTCAGTGGGCCTTGGCAC A GCATCAAACCAAGTTATACCTTC Gln542LeuTCAACACCACCAAGCTTAGGTAAATCAGCTGAGTGTG CAG-CTGCACACTCAGCTGATTTACCTAAGCTTGGTGGTGTTGAGAAGG 3125 TATAACTTGGTTTGATGC TGTGCCAAGGCCCACTGAGGATTC ACACAGCCCACGAAGGAGTGGTTATGCAACATCTCCC CTTGGCAC AGCATCAAA 3126 TTTGATGC T GTGCCAAG 3127 Non-polyposisCCTTCGTGGGCTGTGTGAATCCTCAGTGGGCCTTGGCACAG 3128 colorectal cancerCATCAAACCAAGTTATACC T TCTCAACACCACCAAGCTTAGGT Leu549ProAAATCAGCTGAGTGTGTGAACAAGCAGAGCTACTACA CTT-CCTTGTAGTAGCTCTGCTTGTTCACACACTCAGCTGATTTACCTAA 3129 GCTTGGTGGTGTTGAGA AGGTATAACTTGGTTTGATGCTGTG CCAAGGCGCACTGAGGATTCACACAGCCCACGAAGG GTTATACC TTCTCAACA 3130 TGTTGAGA A GGTATAAC 3131 Non-polyposisTGGGCTGTGTGAATCCTCAGTGGGCCTTGGCACAGCATCAAA 3132 colorectal cancerCCAAGTTATACCTTCTCAACACCACCAAGCTTAGGTAAATCAG Asn55TThrCTGAGTGTGTGAACAAGCAGAGCTACTACAACAATG AAC-ACCCATTGTTGTAGTAGCTCTGCTTGTTCACACACTCAGCTGATTT 3133 ACCTAAGCTTGGTGGTG TTGAGAAGGTATAACTTGGTTTGATG CTGTGCCAAGGCCCACTGAGGATTCACACAGCCCA CCTTCTCA ACACCACCA 3134 TGGTGGTG T TGAGAAGG 3135 Non-polyposisATGAATTCAGCTTTTCCTTAAAGTCACTTCATTTTTATTTTCAG 3136 colorectal cancerTGAAGAACTGTTCTAC C AGATACTCATTTATGATTTTGCCAATT Gln562TermTTGGTGTTCTCAGGTTATCGGTAAGTTTAGATC CAG-TAGGATCTAAACTTACCGATAACCTGAGAACACCAAAATTGGCAAA 3137 ATCATAAATGAGTATCT GGTAGAACAGTTCTTCACTGAAAATA AAAATGAAGTGACTTTAAGGAAAAGCTGAATTCAT TGTTCTAC CAGATACTC 3138 GAGTATCT G GTAGAACA 3139 Non-polyposisGCTTTTCCTTAAAGTCACTTCATTTTTATTTTCAGTGAAGAACT 3140 colorectal cancerGTTCTACCAGATACTC A TTTATGATTTTGCCAATTTTGGTGTTC Ile565PheTCAGGTTATCGGTAAGTTTAGATCCTTTTCACT ATT-TTTAGTGAAAAGGATCTAAACTTACCGATAACCTGAGAACACCAAA 3141 ATTGGCAAAATCATAAA TGAGTATCTGGTAGAACAGTTCTTCA CTGAAAATAAAAATGAAGTGACTTTAAGGAAAAGC AGATACTC ATTTATGAT 3142 ATCATAAA T GAGTATCT 3143 Non-polyposisTTTTCAGTGAAGAACTGTTCTACCAGATACTCATTTATGATTTT 3144 colorectal cancerGCCAATTTTGGTGTTC T CAGGTTATCGGTAAGTTTAGATCCTT Leu574ProTTCACTTCTGAAATTTCAACTGATCGTTTCTGAA CTC-CCCTTCAGAAACGATCAGTTGAAATTTCAGAAGTGAAAAGGATCTA 3145 AACTTACCGATAACCTG AGAACACCAAAATTGGCAAAATCATA AATGAGTATCTGGTAGAACAGTTGTTCACTGAAAA TGGTGTTC TCAGGTTAT 3146 ATAACCTG A GAACACCA 3147 Non-polyposisTGGATGCTCCGTTTAAAGCTTGCTCCTTCATGTTCTTGCTTCTT 3148 colorectal cancerCCTAGGAGCCAGCACCG C TCTTTGACCTTGCCATGCTTGCCT Leu582ValTAGATAGTCCAGAGAGTGGCTGGACAGAGGAAGATG CTC-GTCCATCTTCCTCTGTCCAGCCACTCTCTGGACTATCTAAGGCAA 3149 GCATGGCAAGGTCAAAGA GCGGTGCTGGCTCCTAGGAAGAA GCAAGAACATGAAGGAGCAAGCTTTAACGGAGCATCCA CAGCACCG CTCTTTGAC 3150 GTCAAAGA G CGGTGCTG 3151 Non-polyposisTGCTTGCCTTAGATAGTCCAGAGAGTGGCTGGACAGAGGAAG 3152 colorectal cancerATGGTCCCAAAGAAGGAC T TGCTGAATACATTGTTGAGTTTCT Leu607HisGAAGAAGAAGGCTGAGATGCTTGCAGACTATTTCTC CTT-CATGAGAAATAGTCTGCAAGCATCTCAGCCTTCTTCTTCAGAAACT 3153 CAACAATGTATTCAGCA AGTCCTTCTTTGGGACCATCTTCCTC TGTCCAGCCACTCTCTGGACTATCTAAGGCAAGCA AGAAGGAC TTGCTGAAT 3154 ATTCAGCA A GTCCTTCT 3155 Non-polyposisACAGAGGAAGATGGTCCCAAAGAAGGACTTGCTGAATACATT 3156 colorectal cancerGTTGAGTTTCTGAAGAAG A AGGCTGAGATGCTTGCAGACTAT Lys618TermTTCTCTTTGGAAATTGATGAGGTGTGACAGCCATTCT AAG-TAGAGAATGGCTGTCACACCTCATCAATTTCCAAAGAGAAATAGTC 3157 TGCAAGCATCTCAGCCT TCTTCTTCAGAAACTCAACAATGTAT TCAGCAAGTCCTTCTTTGGGACCATCTTCCTCTGT TGAAGAAG AAGGCTGAG 3158 CTCAGCCT T CTTCTTCA 3159 Non-polyposisCAGAGGAAGATGGTCCCAAAGAAGGACTTGCTGAATACATTG 3160 colorectal cancerTTGAGTTTCTGAAGAAGA A GGCTGAGATGCTTGCAGACTATTT Lys618ThrCTCTTTGGAAATTGATGAGGTGTGACAGCCATTCTT AAG-ACGAAGAATGGCTGTCACACCTCATCAATTTCCAAAGAGAAATAGT 3161 CTGCAAGCATCTCAGCC TTCTTCTTCAGAAACTCAACAATGTA TTCAGCAAGTCCTTCTTTGGGACCATCTTCCTCTG GAAGAAGA AGGCTGAGA 3162 TCTCAGCC T TCTTCTTC 3163 Non-polyposisTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGAC 3164 colorectal cancerTGCCTATCTTCATTCTTC G ACTAGCCACTGAGGTCAGTGATCA Arg659LeuAGCAGATACTAAGCATTTCGGTACATGCATGTGTGC CGA-CTAGCACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCAC 3165 TGACCTCAGTGGCTAGT CGAAGAATGAAGATAGGCAGTCCCT CCAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTA CATTCTTC GACTAGCCA 3166 TGGCTAGT C GAAGAATG 3167 Non-polyposisTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGAC 3168 colorectal cancerTGCCTATCTTCATTCTTC G ACTAGCCACTGAGGTCAGTGATCA Arg659ProAGCAGATACTAAGCATTTCGGTACATGCATGTGTGC CGA-CCAGCACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCAC 3169 TGACCTCAGTGGCTAGT CGAAGAATGAAGATAGGCAGTCCCT CCAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTA CATTCTTC GACTAGCCA 3170 TGGCTAGT C GAAGAATG 3171 Non-polyposisTTACCCCTTCTGATTGACAACTATGTGCCCCCTTTGGAGGGA 3172 colorectal cancerCTGCCTATCTTCATTCTT C GACTAGCCACTGAGGTCAGTGATC Arg659TermAAGCAGATACTAAGCATTTCGGTACATGCATGTGTG CGA-TGACACACATGCATGTACCGAAATGCTTAGTATCTGCTTGATCACT 3173 GACCTCAGTGGCTAGTC GAAGAATGAAGATAGGCAGTCCCTC CAAAGGGGGCACATAGTTGTCAATCAGAAGGGGTAA TCATTCTT CGACTAGCC 3174 GGCTAGTC G AAGAATGA 3175 Non-polyposisTTGGACCAGGTGAATTGGGACGAAGAAAAGGAATGTTTTGAA 3176 colorectal cancerAGCCTCAGTAAAAGAATGC G CTATGTTCTATTCCATCCGGAAG Ala68TThrCAGTACATATCTGAGGAGTCGACCCTCTCAGGCCAGC GCT-ACTGCTGGCCTGAGAGGGTCGACTCCTCAGATATGTACTGCTTCC 3177 GGATGGAATAGAACATAG CGCATTCTTTACTGAGGCTTTCAAA ACATTCCTTTTCTTCGTCCCAATTCACCTGGTCCAA AAGAATGC GCTATGTTC 3178 GAACATAG C GCATTCTT 3179 Non-polyposisAGGCTTATGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGG 3180 colorectal cancerCTCCATTCCAAACTCCT G GAAGTGGACTGTGGAACACATTGT Trp712TermCTATAAAGCCTTGCGCTCACACATTCTGCCTCCTAA TGG-TAGTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATAGACAATG 3181 TGTTCCACAGTCCACTTC CAGGAGTTTGGAATGGAGCCAGGC ACTTCACTCTGGAAAACACATTAGATGTCATAAGCCT AAACTCCT GGAAGTGGA 3182 TCCAGTTC C AGGAGTTT 3183 Non-polyposisATGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCAT 3184 colorectal cancerTCCAAACTCCTGGAAGT G GACTGTGGAACACATTGTCTATAAA Trp714TermGCCTTGCGCTCACACATTCTGCCTCCTAAACATTT TGG-TAGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATAG 3185 ACAATGTGTTCCACAGTC CACTTCCAGGAGTTTGGAATGGAG CCAGGCACTTCACTCTGGAAAACACATTAGATGTCAT CTGGAAGT GGACTGTGG 3186 CCACAGTC C ACTTCCAG 3187 Non-polyposisTGACATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCATT 3188 colorectal cancerCCAAACTCCTGGAAGTG G ACTGTGGAACACATTGTCTATAAA Trp714TermGCCTTGCGCTCACACATTGTGCCTCCTAAACATTTC TGG-TGAGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTTTATA 3189 GACAATGTGTTCCACAGT CCACTTCCAGGAGTTTGGAATGGA GCCAGGCACTTCACTCTGGAAAACACATTAGATGTCA TGGAAGTG GACTGTGGA 3190 TCCACAGT C CACTTCCA 3191 Non-polyposisATCTAATGTGTTTTCCAGAGTGAAGTGCCTGGCTCCATTCCAA 3192 colorectal cancerACTCCTGGAAGTGGACT G TGGAACACATTGTCTATAAAGCCTT Val716MetGCGCTCACACATTCTGCCTCCTAAACATTTCACAG GTG-ATGCTGTGAAATGTTTAGGAGGCAGAATGTGTGAGCGCAAGGCTT 3193 TATAGACAATGTGTTCCA CAGTCCACTTCCAGGAGTTTGGAAT GGAGCCAGGCACTTCACTCTGGAAAACACATTAGAT AGTGGACT GTGGAACAC 3194 GTGTTCCA C AGTCCACT 3195 Non-polyposisGAGTGAAGTGCCTGGCTCCATTCCAAACTCCTGGAAGTGGAC 3196 colorectal cancerTGTGGAACACATTGTCTA T AAAGCCTTGCGCTCACACATTCTG Tyr72TTermCCTCCTAAACATTTCACAGAAGATGGAAATATCCTG TAT-TAACAGGATATTTCCATCTTCTGTGAAATGTTTAGGAGGCAGAATG 3197 TGTGAGCGCAAGGCTTT ATAGACAATGTGTTCCACAGTCCAC TTCCAGGAGTTTGGAATGGAGCCAGGCACTTCACTC ATTGTCTA TAAAGCCTT 3198 AAGGCTTT A TAGACAAT 3199 Non-polyposisCTAAACATTTCACAGAAGATGGAAATATCCTGCAGCTTGCTAA 3200 colorectal cancerCCTGCCTGATCTATACA A AGTCTTTGAGAGGTGTTAAATATGG Lys751ArgTTATTTATGCACTGTGGGATGTGTTCTTCTTTCTC AAA-AGAGAGAAAGAAGAACACATCCCACAGTGCATAAATAACCATATTT 3201 AACACCTCTCAAAGACT TTGTATAGATCAGGCAGGTTAGCAAG CTGCAGGATATTTCCATCTTCTGTGAAATGTTTAG TCTATACA AAGTCTTTG 3202 CAAAGACT T TGTATAGA 3203 Non-polyposisACAGAAGATGGAAATATCCTGCAGCTTGCTAACCTGCCTGAT 3204 colorectal cancerCTATACAAAGTCTTTGAG A GGTGTTAAATATGGTTATTTATGCA Arg755TrpCTGTGGGATGTGTTCTTCTTTCTCTGTATTCCGAT AGG-TGGATCGGAATACAGAGAAAGAAGAACACATCCCACAGTGCATAA 3205 ATAACCATATTTAACACC TCTCAAAGACTTTGTATAGATCAGG CAGGTTAGCAAGCTGCAGGATATTTCCATCTTCTGT TCTTTGAG AGGTGTTAA 3206 TTAACACC T CTCAAAGA 3207

EXAMPLE 18 Human Mismatch Repair—MSH2

[0139] The human MSH2 gene is homologous to the bacterial mutS gene,which is involved in mismatch repair. Mutations in the MSH2 gene havebeen identified in a variety of cancers, including, for example, ovariantumors, colorectal cancer, endometrial cancer, uterine cancer. Theattached table discloses the correcting oligonucleotide base sequencesfor the MSH2 oligonucleotides of the invention. TABLE 25 MSH2 Mutationsand Genome-Correcting Oligos Clinical Phenotype & SEQ ID MutationCorrecting Oligos NO: Non polyposisTTTTCCACAAAAGACATTTATCAGGACCTCAACCGGTTGTTGA 3208 colorectal cancerAAGGCAAAAAGGGAGAG C AGATGAATAGTGCTGTATTGCCAG Gln252TermAAATGGAGAATCAGGTACATGGATTATAAATGTGAA CAG-TAGTTCACATTTATAATCCATGTACCTGATTCTCCATTTCTGGCAAT 3209 ACAGCACTATTCATCT GCTCTCCCTTTTTGCCTTTCAACAACC GGTTGAGGTCCTGATAAATGTCTTTTGTGGAAAA AGGGAGAG CAGATGAAT 3210 ATTCATCT G CTCTCCCT 3211 Non polyposisTCATCACTGTCTGCGGTAATCAAGTTTTTAGAACTCTTATCAG 3212 colorectal cancerATGATTCCAACTTTGGA C AGTTTGAACTGACTACTTTTGACTT Gln288TermCAGCCAGTATATGAAATTGGATATTGCAGCAGTCA CAG-TAGTGACTGCTGCAATATCCAATTTCATATACTGGCTGAAGTCAAA 3213 AGTAGTCAGTTCAAACT GTCCAAAGTTGGAATCATCTGATAAG AGTTCTAAAAACTTGATTACCGCAGACAGTGATGA ACTTTGGA CAGTTTGAA 3214 TTCAAACT G TCCAAAGT 3215 Non polyposisAACTTTGGACAGTTTGAACTGACTACTTTTGACTTCAGCCAGT 3216 colorectal cancerATATGAAATTGGATATT G CAGCAGTCAGAGCCCTTAACCTTTT Ala305ThrTCAGGTAAAAAAAAAAAAAAAAAAAAAAAAAAAGG GCA-ACACCTTTTTTTTTTTTTTTTTTTTTTTTTTTACCTGAAAAAGGTTAAG 3217 GGCTCTGACTGCTG CAATATCCAATTTCATATACTGGCTGAAG TCAAAAGTAGTCAGTTCAAACTGTCCAAAGTT TGGATATT GCAGCAGTC 3218 GACTGCTG C AATATCCA 3219 Non polyposisAGCTTGCCATTCTTTCTATTTTATTTTTTGTTTACTAGGGTTCT 3220 colorectal cancerGTTGAAGATACCACTG G CTCTCAGTCTCTGGCTGCCTTGCTG Gly322AspAATAAGTGTAAAACCCCTCAAGGACAAAGACTTGT GGC-GACACAAGTCTTTGTCCTTGAGGGGTTTTACACTTATTCAGCAAGG 3221 CAGCCAGAGACTGAGAG CCAGTGGTATCTTCAACAGAACCCT AGTAAACAAAAAATAAAATAGAAAGAATGGCAAGGT TACCACTG GCTCTCAGT 3222 ACTGAGAG C CAGTGGTA 3223 Non polyposisTTGCCATTCTTTCTATTTTATTTTTTGTTTACTAGGGTTCTGTTG 3224 colorectal cancerAAGATACCACTGGCT C TCAGTCTCTGGCTGCCTTGCTGAATA Ser323CysAGTGTAAAACCCCTCAAGGACAAAGACTTGTTAA TCT-TGTTTAACAAGTCTTTGTCCTTGAGGGGTTTTACACTTATTCAGCA 3225 AGGCAGCCAGAGACTGAGA GCCAGTGGTATCTTCAACAGAAC CCTAGTAAACAAAAAATAAAATAGAAAGAATGGCAA CACTGGCT CTCAGTCTC 3226 GAGACTGA G AGCCAGTG 3227 Non polyposisGTGGAAGCTTTTGTAGAAGATGCAGAATTGAGGCAGACTTTA 3228 colorectal cancerCAAGAAGATTTACTTCGT C GATTCCCAGATCTTAACCGACTTG Arg383TermCCAAGAAGTTTCAAAGACAAGCAGCAAACTTACAAG CGA-TGACTTGTAAGTTTGCTGCTTGTCTTGAAACTTCTTGGCAAGTCG 3229 GTTAAGATCTGGGAATC GACGAAGTAAATCTTCTTGTAAAGTC TGCCTCAATTCTGCATCTTCTACAAAAGCTTCCAC TACTTCGT CGATTCCCA 3230 TGGGAATC G ACGAAGTA 3231 Non polyposisCAAGAAGATTTACTTCGTCGATTCCCAGATCTTAACCGACTTG 3232 colorectal cancerCCAAGAAGTTTCAAAGA C AAGCAGCAAACTTACAAGATTGTTA Gln397TermCCGACTCTATCAGGGTATAAATCAACTACCTAATG CAA-TAACATTAGGTAGTTGATTTATACCCTGATAGAGTCGGTAACAATC 3233 TTGTAAGTTTGCTGCTT GTCTTTGAAACTTCTTGGCAAGTCGG TTAAGATCTGGGAATCGACGAAGTTAAATCTTCTTG TTCAAAGAC AAGCAGCA 3234 TGCTGCTT G TCTTTGAA 3235 Non polyposisGATCTTAACCGACTTGCCAAGAAGTTTCAAAGACAAGCAGCA 3236 colorectal cancerAACTTACAAGATTGTTAC C GACTCTATCAGGGTATAAATCAAC Arg406TermTACCTAATGTTATACAGGCTCTGGAAAAACATGAAG CGA-TGACTTCATGTTTTTCCAGAGCCTGTATAACATTAGGTAGTTGATTT 3237 ATACCCTGATAGAGTC GGTAACAATCTTGTAAGTTTGCTGCTT GTCTTTGAAACTTCTTGGCAAGTGGGTTAAGATC ATTGTTAC CGACTCTAT 3238 ATAGAGTC G GTAACAAT 3239 Non polyposisGCAAACTTACAAGATTGTTACCGACTCTATCAGGGTATAAATC 3240 colorectal cancerAACTACCTAATGTTATAC A GGCTCTGGAAAAACATGAAGGTAA Gln419TermCAAGTGATTTTGTTTTTTTTGTTTTCCTTCAACTCA CAG-TAGTGAGTTGAAGGAAAACAAAAAAACAAAATCACTTGTTACCTTC 3241 ATGTTTTTCCAGAGCCT GTATAACATTAGGTAGTTGATTTATAC CCTGATAGAGTCGGTAACAATCTTGTAAGTTGC ATGTTATA CAGGCTGTG 3242 CAGAGCCT G TATAACAT 3243 Non polyposisTATTCTGTAAAATGAGATCTTTTTATTTGTTTGTTTTACTACTTT 3244 colorectal cancerCTTTTAGGAAACAC C AGAATTATTGTTGGCAGTTTTTGTGA Gln429TermCTCCTCTTACTGATCTTCGTTCTGACTTCTCCA CAG-TAGTGGAGAAGTCAGAACGAAGATCAGTAAGAGGAGTCACAAAAA 3245 CTGCCAACAATAATTTCT GGTGTTTTCCTAAAAGAAAGTAGTA AAACAAACAAATAAAAAGATCTCATTTTACAGAATA GAAAACAC CAGAAATTA 3246 TAATTTCT G GTGTTTTC 3247 Non polyposisCTCCTCTTACTGATCTTCGTTCTGACTTCTCCAAGTTTCAGGA 3248 colorectal cancerAATGATAGAAACAACTT T AGATATGGATCAGGTATGCAATATA Leu458TermCTTTTTAATTTAAGCAGTAGTTATTTTTAAAAAGC TTA-TGAGCTTTTTAAAAATAACTACTGCTTAAATTAAAAAGTATATTGCA 3249 TACCTGATCCATATCT AAAGTTGTTTCTATCATTTCCTGAAACT TGGAGAAGTCAGAACGAAGATCAGTAAGAGGAG AACAACTT TAGATATGG 3250 CCATATCT A AAGTTGTT 3251 Non polyposisTTTCTTCTTGATTATCAAGGCTTGGACCCTGGCAAACAGATTA 3252 colorectal cancerAACTGGATTCCAGTGCA C AGTTTGGATATTACTTTCGTGTAAC Gln518TermCTGTAAGGAAGAAAAAGTCCTTCGTAACAATAAAA CAG-TAGTTTTATTGTTACGAAGGACTTTTTCTTCCTTACAGGTTACACGA 3253 AAGTAATATCCAAACT GTGCACTGGAATCCAGTTTAATCTGTT TGCCAGGGTCCAAGCCTTGATAATCAAGAAGAAA CCAGTGCA CAGTTTGGA 3254 TCCAAACT G TGCACTGG 3255 Non polyposisGCTTGGACCCTGGCAAACAGATTAAACTGGATTCCAGTGCAC 3256 colorectal cancerAGTTGGATATTACTTTC G TGTAACCTGTAAGGAAGAAAAAGT Arg524ProCCTTCGTAACAATAAAAACTTTAGTACTGTAGATAT CGT-CCTATATCTACAGTACTAAAGTTTTTATTGTTACGAAGGACTTTTTC 3257 TTCCTTACAGGTTACA CGAAAGTAATATCCAAACTGTGCACTG GAATCCAGTTTAATCTGTTTGCCAGGGTCCAAGC TTACTTTC GTGTAACCT 3258 AGGTTACA C GAAAGTAA 3259 Non polyposisTTAATATTTTTAATAAAACTGTTATTTCGATTTGCAGCAAATTGA 3260 colorectal cancerCTTCTTTAAATGAAG A GTATACCAAAAATAAAACAGAATATGAA Glu562ValGAAGCCCAGGATGCCATTGTTAAAGAAATTGT GAG-GTGACAATTTCTTAACAATGGCATCCTGGGCTTCTTCATATTCTGT 3261 TTTATTTTTGGTATAC TCTTCATTTAAAGAAGTCAATTTGCTGC AAATCGAAATAACAGTATTATTAAAAATATTAA AAATGAAG AGTATACCA 3262 TGGTATAC T CTTCATTT 3263 GliomaAATGAAGAGTATACCAAAAATAAAACAGAATATGAAGAAGCCC 3264 Glu580TermAGGATGCCATTGTTAAA G AAATTGTCAATATTTCTTCAGGTAAA GAA-TAACTTAATAGAACTAATAATGTTCTGAATGTCACCTAGGTGACATTCAGAACATTATTAGTTCTATTAAGTTTACCTGAA 3265 GAAATATTGACAATTT CTTTAACAATGGCATCCTGGGCTTCTT CATATTCTGTTTTATTTTTGGTATACTCTTCATT TTGTTAAA GAAATTGTC 3266 GACAATTT C TTTAACAA 3267 Non polyposisTGTTTTTATTTTTATACAGGCTATGTAGAACCAATGCAGACACT 3268 colorectal cancerCAATGATGTGTTAGCT C AGCTAGATGCTGTTGTCAGCTTTGCT Gln60TTermCACGTGTCAAATGGAGCACCTGTTCCATATGTAC CAG-TAGGTACATATGGAACAGGTGCTCCATTTGACACGTGAGCAAAGC 3269 TGACAACAGCATCTAGCT GAGCTAACACATCATTGAGTGTCTG CATTGGTTCTACATAGCCTGTATAAAAATAAAAAACA TGTTAGCTC AGCTAGAT 3270 ATCTAGCT G AGCTAACA 3271 Non polyposisAGCTCAGCTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAAT 3272 colorectal cancerGGAGCACCTGTTCCATA T GTACGACCAGCCATTTTGGAGAAA Tyr619TermGGACAAGGAAGAATTATATTAAAAGCATCCAGGCAT TAT-TAGATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTTCTCCA 3273 AAATGGCTGGTCGTAC ATATGGAACAGGTGCTCCATTTGACA CGTGAGCAAAGCTGACAACAGCATCTAGCTGAGCT GTTCCATA TGTACGACC 3274 GGTCGTAC A TATGGAAC 3275 Non polyposisCAGCTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAATGGA 3276 colorectal cancerGCACCTGTTCGATATGTA C GACCAGCCATTTTGGAGAAAGGA Arg62TTermCAAGGAAGAATTATATTAAAAGCATCCAGGCATGCTT CGA-TGAAAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTCCTTTC 3277 TCCAAAATGGCTGGTC GTACATATGGAACAGGTGCTCCATTT GACACGTGAGCAAAGCTGACAACAGCATCTAGCTG CATATGTA CGACCAGCC 3278 GGCTGGTC G TACATATG 3279 Non polyposisTAGATGCTGTTGTCAGCTTTGCTCACGTGTCAAATGGAGCAC 3280 colorectal cancerCTGTTCCATATGTACGAC C AGCCATTTTGGAGAAAGGACAAG Pro622LeuGAAGAATTATATTAAAAGCATCCAGGCATGCTTGTGT CCA-CTAACACAAGCATGCCTGGATGCTTTTAATATAATTCTTCCTTGTC 3281 CTTTCTCCAAAATGGCT GGTCGTACATATGGAACAGGTGCTC CATTTGAGACGTGAGCAAAGCTGACAACAGCATCTA TGTACGAC CAGCCATTT 3282 AAATGGCT G GTCGTACA 3283 Non polyposisCCTGTTCCATATGTACGACCAGCCATTTTGGAGAAAGGACAA 3284 colorectal cancerGGAAGAATTATATTAAAA G CATCCAGGCATGCTTGTGTTGAAG Ala636ProTTCAAGATGAAATTGCATTTATTCCTAATGACGTAT GCA-CCAATACGTCATTAGGAATAAATGCAATTTCATCTTGAACTTCAACA 3285 CAAGCATGCCTGGATG CTTTTAATATAATTCTTCCTTGTGCTTT CTCCAAAATGGCTGGTCGTACATATGGAACAGG TATTAAAA GCATCCAGG 3286 CCTGGATG C TTTTAATA 3287 Non polyposisATGTACGACCAGCCATTTTGGAGAAAGGACAAGGAAGAATTA 3288 colorectal cancerTATTAAAAGCATCCAGGC A TGCTTGTGTTGAAGTTCAAGATGA His639ArgAATTGCATTTATTCCTAATGACGTATACTTTGAAAA CAT-CGTTTTTCAAAGTATACGTCATTAGGAATAAATGCAATTTCATCTTG 3289 AACTTCAACACAAGCA TGCCTGGATGCTTTTAATATAATTCTTC CTTGTCCTTTCTCCAAAATGGCTGGTGGTACAT ATCCAGGC ATGCTTGTG 3290 CACAAGCA T GCCTGGAT 3291 Non polyposisTATGTACGACCAGCCATTTTGGAGAAAGGACAAGGAAGAA 3292 colorectal cancerATATTAAAAGCATCCAGG C ATGCTTGTGTTGAAGTTCAAGATG His639TyrAAATTGCATTTATTCCTAATGACGTATACTTTGAAA CAT-TATTTTCAAAGTATACGTCATTAGGAATAAATGCAATTTCATCTTGA 3293 ACTTCAACACAAGCAT GCCTGGATGCTTTTAATATAATTCTTC CTTGTCCTTTCTCCAAAATGGCTGGTCGTACATA CATCCAGG CATGCTTGT 3294 ACAAGCAT G CCTGGATG 3295 Non polyposisAAAGGACAAGGAAGAATTATATTTAAAAGCATCCAGGCATGCTT 3296 colorectal cancerGTGTTGAAGTTCAAGAT G AAATTGCATTTATTCCTAATGACGT Glu647LysATACTTTGAAAAAGATAAACAGATGTTCCACATCA GAA-AAATGATGTGGAACATCTGTTTATCTTTTTCAAAGTATACGTCATTA 3297 GGAATAAATGCAATTT CATCTTGAACTTCAACACAAGCATGCC TGGATGCTTTTAATATAATTCTTCCTTGTCCTTT TTCAAGAT GAAATTGCA 3298 TGCAATTT C ATCTTGAA 3299 Non polyposisATCCAGGCATGCTTGTGTTGAAGTTCAAGATGAAATTGCATTT 3300 colorectal cancerATTCCTAATGACGTATA C TTTGAAAAAGATAAACAGATGTTCCA Tyr656TermCATCATTACTGGTAAAAAACCTGGTTTTTGGGCT TAC-TAGAGCCCAAAAACCAGGTTTTTTACCAGTAATGATGTGGAACATC 3301 TGTTTATCTTTTTCAAA GTATACGTCATTAGGAATAAATGCAAT TTCATCTTGAACTTCAACACAAGCATGCCTGGAT GACGTATA CTTTGAAAA 3302 TTTTCAAA G TATACGTC 3303 Non polyposisGAAAAGAAGTTTAAAATCTTGCTTTCTGATATAATTTGTTTTGTA 3304 colorectal cancerGGCCCCAATATGGGAG G TAAATCAACATATATTCGACAAACT Gly674AspGGGGTGATAGTACTCATGGCCCAAATTGGGTGTTT GGT-GATAAACACCCAATTTGGGCCATGAGTACTATCACCCCAGTTTGTC 3305 GAATATATGTTGATTTA CCTCCCATATTGGGGCCTACAAAACA AATTATATCAGAAAGCAAGATTTTAAACTTCTTTC TATGGGAG GTAAATCAA 3306 TTGATTTA C CTCCCATA 3307 Non polyposisTTGCTTTCTGATATAATTTGTTTTGTAGGCCCCAATATGGGAG 3308 colorectal cancerGTAAATCAACATATATT C GACAAACTGGGGTGATAGTACTCAT Arg680TermGGCCCAAATTGGGTGTTTTGTGCCATGTGAGTCAG CGA-TGACTGACTCACATGGCACAAAACACCCAATTTGGGCCATGAGTA 3309 CTATCACCCCAGTTTGTC GAATATATGTTGATTTACCTCCCAT ATTGGGGCCTACAAAACAAATTATATCAGAAAGCAA CATATATT CGACAAACT 3310 AGTTTGTC G AATATATG 3311 Non polyposisATGGGAGGTAAATCAACATATATTCGACAAACTGGGGTGATA 3312 colorectal cancerGTACTCATGGCCCAAATT G GGTGTTTTGTGCCATGTGAGTCA Gly692ArgGCAGAAGTGTCCATTGTGGACTGCATCTTAGCCCGAG GGG-CGGCTCGGGCTAAGATGCAGTCCACAATGGACACTTCTGCTGACT 3313 CACATGGCACAAAACACC CAATTTGGGCCATGAGTACTATCA CCCCAGTTTGTCGAATATATGTTGATTTACCTCCCAT CCCAAATT GGGTGTTTT 3314 AAAACACC C AATTTGGG 3315 Non polyposisACATATATTCGACAAACTGGGGTGATAGTACTCATGGCCCAAA 3316 colorectal cancerTTGGGTGTTTTGTGCCA T GTGAGTCAGCAGAAGTGTCCATTG Cys697ArgTGGACTGCATCTTAGCCCGAGTAGGGGCTGGTGACA GT-CGTTGTCACCAGCCCCTACTCGGGCTAAGATGCAGTCCACAATGG 3317 ACACTTCTGCTGACTCAC ATGGCACAAAACACCCAATTTGGG CCATGAGTACTATCACCCCAGTTTGTCGAATATATGT TTGTGCCA TGTGAGTCA 3318 TGACTCAC A TGGCACAA 3319 Non polyposisCATATATTCGACAAACTGGGGTGATAGTACTCATGGCCCAAAT 3320 colorectal cancerTGGGTGTTTTGTGCCAT G TGAGTCAGCAGAAGTGTCCATTGT Cys697PheGGACTGCATCTTAGCCCGAGTAGGGGCTGGTGACAG TGT-TTTCTGTCACCAGCCCCTACTCGGGCTAAGATGCAGTCCACAATG 3321 GACACTTCTGCTGACTCA CATGGCACAAAACACCCAATTTGG GCCATGAGTACTATCACCCCAGTTTGTCGAATATATG TGTGCCAT GTGAGTCAG 3322 CTGACTCA C ATGGCACA 3323 Non polyposisGAGTCAGCAGAAGTGTCCATTGTGGACTGCATCTTAGCCCGA 3324 colorectal cancerGTAGGGGCTGGTGACAGT C AATTGAAAGGAGTCTCCACGTTC Gln718TermATGGCTGAAATGTTGGAAACTGCTTCTATCCTCAGGT CAA-TAAACCTGAGGATAGAAGCAGTTTCCAACATTTCAGCCATGAACG 3325 TGGAGACTCCTTTCAATT GACTGTCACCAGCCCCTACTCGGG CTAAGATGCAGTCCACAATGGACACTTCTGCTGACTC GTGACAGT CAATTGAAA 3326 TTTCAATT G ACTGTCAC 3327 Non polyposisCCAATCAGATACCAACTGTTAATAATCTACATGTCACAGCACT 3328 colorectal cancerCACCACTGAAGAGACCT T AACTATGCTTTATCAGGTGAAGAAA Leu81TTermGGTATGTACTATTGGAGTACTCTAAATTCAGAACT TTA-TGAAGTTCTGAATTTAGAGTACTCCAATAGTACATACCTTTCTTCAC 3329 CTGATAAAGCATAGTT AAGGTCTCTTCAGTGGTGAGTGCTGT GACATGTAGATTATTAACAGTTGGTATCTGATTGG AGAGACCT TAACTATGC 3330 GCATAGTT A AGGTCTCT 3331 Non polyposisTTCCCCAAATTTCTTATAGGTGTCTGTGATCAAAGTTTTGGGA 3332 colorectal cancerTTCATGTTGCAGAGCTT G CTAATTTCCCTAAGCATGTAATAGA Ala834ThrGTGTGCTAAACAGAAAGCCCTGGAACTTGAGGAGT GCT-ACTACTCCTCAAGTTCCAGGGCTTTCTGTTTAGCACACTCTATTAC 3333 ATGCTTAGGGAAATTAG CAAGCTCTGCAACATGAATCCCAAAA CTTTGATCACAGACACCTATAAGAAATTTGGGGAA CAGAGCTT GCTAATTTC 3334 GAAATTAG C AAGCTCTG 3335 Non polyposisATAGAGTGTGCTTAAACAGAAAGCCCTGGAACTTGAGGAGTTT 3336 colorectal cancerCAGTATATTGGAGAATCG C AAGGATATGATATCATGGAACCAG Gln86TTermCAGCAAAGAAGTGCTATCTGGAAAGAGAGGTTTGTC CAA-TAAGACAAACCTCTCTTTCCAGATAGCACTTCTTTGCTGCTGGTTC 3337 CATGATATCATATCCTT GCGATTCTCCAATATACTGAAACTCCT CAAGTTCCAGGGCTTTCTGTTTAGCACACTCTAT GAGAATCG CAAGGATAT 3338 ATATCCTT G CGATTCTC 3339 Non polyposisAGGAGTTCCTGTCCAAGGTGAAACAAATGCCCTTTACTGAAAT 3340 colorectal cancerGTCAGAAGAAAACATCA C AATAAAGTTAAAACAGCTAAAAGCT Thr905ArgGAAGTAATAGCAAAGAATAATAGCTTTGTAAATGA ACA-AGATCATTTACAAAGCTATTATTCTTTGCTATTACTTCAGCTTTTAG 3341 CTGTTTTAACTTTATTT GTGATGTTTTCTTCTGACATTTCACTAA AGGGCATTTGTTTCACCTTGGACAGGAACTCCT AAACATCA CAATAAAGT 3342 ACTTTATT G TGATGTTT 3343

EXAMPLE19 Human Mismatch Repair—MSH6

[0140] The human MSH6 gene is homologous to the bacterial mutS gene,which is involved in mismatch repair. Mutations in the MSH6 gene havebeen identified in a variety of cancers, including particularlyhereditary nonpolyposis colorectal cancer. The attached table disclosesthe correcting oligonucleotide base sequences for the MSH6oligonucleotides of the invention. TABLE 26 MSH6 Mutations andGenome-Correcting Oligos Clinical Phenotype & SEQ ID Mutation CorrectingOligos NO: Non-polyposis GGAAATCAGTCCGTGTTCATGTACAGTTTTTTGATGACAGCCC3344 colorectal cancer AACAAGGGGCTGGGTTA G CAAAAGGCTTTTAAAGCCATATACSer144lle AGGTAAGAGTCACTAGTGCCATGTGTGTGTGTTTGT AGC-ATCACAAACACACACACATGGCAGTAGTGACTCTTACCTGTATATG 3345 GCTTTAAAAGCCTTTTG CTAACCCAGCCCCTTGTTGGGCTGT CATCAAAAAACTGTACATGAACACGGACTGATTTCC CTGGGTTA GCAAAAGGC 3346 GCCTTTTG C TAACCCAG 3347 Endometrial cancerCGTGAGCCTCTGCACCCGGCCCTTATTGTTTATAAATACATTT 3348 Ser156TermCTTTCTAGGTTCAAAAT C AAAGGAAGCCCAGAAGGGAGGTCA TCA-TGATTTTTACAGTGCAAAGCCTGAAATACTGAGAGCAATATTGCTCTCAGTATTTCAGGCTTTGCACTGTAAAAATGACCTC 3349 CCTTCTGGGCTTCCTTT GATTTTGAACCTAGAAAGAAATGTAT TTATAAACAATAAGGGCCGGGTGCAGAGGCTCACG TTCAAAAT CAAAGGAAG 3350 CTTCCTTT G ATTTTGAA 3351 Early onset colorectalTTCCAAATTTTGATTTGTTTTTAAATACTCTTTCCTTGCCTGGC 3352 cancerAGGTAGGCACAACTTA C GTAACAGATAAGAGTGAAGAAGATA Tyr214TermATGAAATTGAGAGTGAAGAGGAAGTACAGCCTAAG TAC-TAGCTTAGGCTGTACTTCCTCTTCACTCTCAATTTCATTATCTTCTT 3353 CACTCTTATCTGTTAC GTAAGTTGTGCCTACCTGCCAGGCAA GGAAAGAGTATTTAAAAACAAATCAAAATTTGGAA ACAACTTA CGTAACAGA 3354 TCTGTTAC G TAAGTTGT 3355 Endometrial cancerGAAGAGGAAGTACAGCCTAAGACACAAGGATCTAGGCGAAGT 3356 Arg248TermAGCCGCCAAATAAAAAAAB CGAAGGGTCATATCAGATTCTGAG CGA-TGAAGTGACATTGGTGGCTCTGATGTGGAATTTAAGCCAGCTGGCTTAAATTCCACATCAGAGCCACCAATGTCACTCTCAGA 3357 ATCTGATATGACCCTTC GTTTTTTTATTTGGCGGCTACTTCGC CTAGATCCTTGTGTCTTAGGCTGTACTTCCTCTTC TAAAAAAA CGAAGGGTC 3358 GACCCTTC G TTTTTTTA 3359 Colorectal cancerTTAAGCCAGACACTAAGGAGGAAGGAAGCAGTGATGAAATAA 3360 Ser285IleGCAGTGGAGTGGGGGATA G TGAGAGTGAAGGCCTGAACAGC AGT-ATTCCTGTCAAAGTTGCTCGAAAGCGGAAGAGAATGGTGACGTCACCATTCTCTTCCGCTTTCGAGCAACTTTGACAGGGCTG 3361 TTCAGGCCTTCACTCTCA CTATCCCCCACTCCACTGCTTATTT CATCACTGCTTCCTTCCTCCTTAGTGTCTGGCTTAA GGGGGATA GTGAGAGTG 3362 CACTCTCA C TATCCCCC 3363 Colorectal cancerGAGGAAGATTCTTCTGGCCATACTCGTGCATATGGTGTGTGC 3364 Gly566ArgTTTGTTGATACTTCACTG G GAAAGTTTTTCATAGGTCAGTTTTC GGA-AGAAGATGATCGCCATTGTTCGAGATTTAGGACTCTAGCTAGAGTCCTAAATCTCGAACAATGGCGATCATCTGAAAACTG 3365 ACCTATGAAAAACTTTC CCAGTGAAGTATCAACAAAGCACACA CCATATGCACGAGTATGGCCAGAAGAATCTTCCTC CTTCACTG GGAAAGTTT 3366 AAACTTTC C CAGTGAAG 3367 Non-polyposisGAATTGGCCCTCTCTGCTCTAGGTGGTTGTGTCTTCTACCTC 3368 colorectal cancerAAAAAATGCCTTATTGAT C AGGAGCTTTTATCAATGGCTAATTT Gln698GluTGAAGAATATATTCCCTTGGATTCTGACACAGTCA CAG-GAGTGACTGTGTCAGAATCCAAGGGAATATATTCTTCAAAATTAGC 3369 CATTGATAAAAGCTCCT GATCAATAAGGCATTTTTTGAGGTAG AAGACACAACCACCTAGAGCAGAGAGGGCCAATTC TTATTGAT CAGGAGCTT 3370 AAGCTCCT G ATCAATAA 3371 Endometrial cancerCCCTTGGATTCTGACACAGTCAGCACTACAAGATCTGGTGCT 3372 Gln731TermATCTTCACCAAAGCCTAT C AACGAATGGTGCTAGATGCAGTG CAA-TAAACATTAAACAACTTGGAGATTTTTCTGAATGGAACAATTGTTCCATTCAGAAAAATCTCCAAGTTGTTTAATGTCACTGCA 3273 TCTAGCACCATTCGTT GATAGGCTTTGGTGAAGATAGCACCA GATCTTGTAGTGCTGACTGTGTCAGAATCCAAGGG AAGCCTAT CAACGAATG 3374 CATTCGTT G ATAGGCTT 3375 Colorectal cancerGCCCCACTCTGTAACCATTATGCTATTAATGATCGTCTAGATG 3376 Val800LeuCCATAGAAGACCTCATG G TTGTGCCTGACAAAATCTCCGAAG GTT-CTTTGTAGAGCTTCTAAAGAAGCTTCCAGATCTTGAGATCTCAAGATCTGGAAGCTTCTTTAGAAGCTCTACAACTTCGGA 3377 GATTTTGTCAGGCACAA CCATGAGGTCTTCTATGGCATCTAGA CGATCATTAATAGCATAATGGTTACAGAGTGGGGC ACCTCATG GTTGTGCCT 3378 AGGCACAA C CATGAGGT 3379 Colorectal cancerGTAACCATTATGCTATTAATGATCGTCTAGATGCCATAGAAGA 3380 Asp803GlyCCTCATGGTTGTGCCTGA C AAAATCTCCGAAGTTGTAGAGCT GAC-GGCTCTAAAGAAGCTTCCAGATCTTGAGAGGCTACTCAGCTGAGTAGCCTCTCAAGATCTGGAAGCTTCTTTAGAAGCTCTA 3381 CAACTTCGGAGATTTTG TCAGGCACAACCATGAGGTCTTCTAT GGCATCTAGACGATCATTAATAGCATAATGGTTAC TGTGCCTG ACAAAATCT 3382 AGATTTTG T CAGGCACA 3383 Non-polyposisCTCCCCTGAAGAGTCAGAACCACCCAGACAGCAGGGCTATAA 3384 colorectal cancerTGTATGAAGAAACTACAT A CAGCAAGAAGAAGATTATTGATTT Tyr850CysTCTTTCTGCTCTGGAAGGATTCAAAGTAATGTGTAA TAC-TGCTTACACATTACTTTGAATCCTTCCAGAGCAGAAAGAAAATCAA 3385 TAATCTTCTTCTTGCTG TATGTAGTTTCTTCATACATTATAGCC CTGCTGTCTGGGTGGTTCTGACTCTTCAGGGGAG AACTACAT ACAGCAAGA 3386 TCTTGCTG T ATGTAGTT 3387 Colorectal cancerTATAGTCGAGGGGGTGATGGTCCTATGTGTCGCCCAGTAATT 3388 Pro1087ThrCTGTTGCCGGAAGATACC C CCCCCTTCTTAGAGCTTAAAGGA CCC-ACCTCACGCCATCCTTGCATTACGAAGACTTTTTTTGGAGCTCCAAAAAAAGTCTTCGTAATGCAAGGATGGCGTGATCCTTT 3389 AAGCTCTAAGAAGGGGG GGGTATCTTCCGGCAACAGAATTAC TGGGCGACACATAGGACCATCACCCCCTCGACTATA AAGATACC CCCCCCTTC 3390 GAAGGGGG G GGTATCTT 3391 Non-polyposisACTATAAAATGTCGTACATTATTTTCAACTCACTACCATTCATT 3392 colorectal cancerAGTAGAAGATTATTCT C AAAATGTTGCTGTGCGCCTAGGACAT Gln1258TermATGGTATGTGCAAATTGTTTTTTTCCACAAATTC CAA-TAAGAATTTGTGGAAAAAAACAACTTTGCACACATACCATATGTCCTAG 3393 GCGCACAGCAACATTTT GAGAATAATCTTCTACTAATGAATGG TAGTGAGTTGAAAATAATGTACGACATTTTATAGT ATTATTCT CAAAATGTT 3394 AACATTTT G AGAATAAT 3395

EXAMPLE20 Hyperlipidemia—APOE

[0141] Hyperlipidemia is the abnormal elevation of plasma cholesteroland/or triglyceride levels and it is one of the most common diseases.The human apolipoprotein E protein is involved in the transport ofendogenous lipids and appears to be crucial for both the direct removalof cholesterol-rich LDL from plasma and conversion of IDL particles toLDL particles. Individuals who either lack apolipoprotein E or who arehomozygous for particular alleles of apoE may have have a conditionknown as dysbetalipoproteinemia, which is characterized by elevatedplasma cholesterol and triglyceride levels and an increased risk foratherosclerosis.

[0142] In a comprehensive review of apoE variants, de Knijff et al.,Hum. Mutat. 4:178-194 (1994) found that 30 variants had beencharacterized, including the most common variant, apoE3. To that time,14 apoE variants had been found to be associated with familialdysbetalipoproteinemia. The attached table discloses the correctingoligonucleotide base sequences for the APOE oligonucleotides of theinvention. TABLE 27 APOE Mutations and Genome-Correcting Oligos ClinicalPhenotype & SEQ ID Mutation Correcting Oligos NO: Apolipoprotein ETTGTTCCACACAGGATGCCAGGCCAAGGTGGAGCAAGCGGT 3396 Glu13LysGGAGACAGAGCCGGAGCCC G AGCTGCGCCAGCAGACCGAG cGAG-AAGTGGCAGAGCGGCCAGCGCTGGGAACTGGCACTGGGTCGCTAGCGACCCAGTGCCAGTTCCCAGCGCTGGCCGCTCTGCCAC 3397 TCGGTCTGCTGGCGCAGCT CGGGCTCCGGCTCTGTCTCCAC CGCTTGCTCCACCTTGGCCTGGCATCCTGTGTGGAACAA CGGAGCCC GAGCTGCGC 3398 GCGCAGCT C GGGCTCCG 3399 Apolipoprotein ECAAGGTGGAGCAAGCGGTGGAGACAGAGCCGGAGCCCGAG 3400 Trp20TermCTGCGCCAGCAGACCGAGTG G CAGAGCGGCCAGCGCTGGG TGGc-TGAAACTGGCACTGGGTCGCTTTTGGGATTACCTGCGCTGGGTGCACCCAGCGCAGGTAATCCCAAAAGCGACCCAGTGCCAGTT 3401 CCCAGCGCTGGCCGCTCTG CCACTCGGTCTGCTGGCGCAGC TCGGGCTCCGGCTCTGTCTCCACCGCTTGCTCCACCTTG ACCGAGTG GCAGAGCGG 3402 CCGCTCTG C CACTCGGT 3403 Apolipoprotein ECAGAGCCGGAGCCCGAGCTGCGCCAGCAGACCGAGTGGCA 3404 Leu28ProGAGCGGCCAGCGCTGGGAAC T GGCACTGGGTCGCTTTTGGG CTG-CCGATTACCTGCGCTGGGTGCAGACACTGTCTGAGCAGGTGCATGCACCTGCTCAGACAGTGTCTGCACCCAGCGCAGGTAATCC 3405 CAAAAGCGACCCAGTGCC AGTTCCCAGCGCTGGCCGCTCTG CCACTCGGTCTGCTGGCGCAGCTCGGGCTCCGGCTCTG CTGGGAA CTGGCACTGG 3406 CCAGTGCC A GTTCCCAG 3407 Apolipoprotein ECGGCTGTCCAAGGAGCTGCAGGCGGCGCAGGCCCGGCTGG 3408 Cys112ArgGCGCGGACATGGAGGACGTG T GCGGCCGCCTGGTGCAGTA gTGC-CGCCCGCGGCGAGGTGCAGGCCATGCTCGGCCAGAGCACCGAG GCCTCGGTGCTCTGGCCGAGCATGGCCTGCACCTCGCCGCGG 3409 TACTGCACCAGGCGGCCGC ACACGTCCTCCATGTCCGCGCC CAGCCGGGCCTGCGCCGCCTGCAGCTCCTGGACAGCCG AGGACGTG TGCGGCCGC 3410 GCGGCCGC A CACGTCCT 3411 Apolipoprotein EACATGGAGGACGTGTGCGGCCGCCTGGTGCAGTACCGCGG 3412 Gly127AspCGAGGTGCAGGCCATGCTCG G CCAGAGCACCGAGGAGCTG GGC-GACCGGGTGCGCCTCGCCTCCCACCTGCGCAAGCTGCGTAAGCGCGCTTACGCAGCTTGCGCAGGTGGGAGGCGAGGCGCACCC 3413 GCAGCTCCTCGGTGCTCTGG CCGAGCATGGCCTGCACCTCG CCGCGGTACTGCACCAGGCGGCCGCACACGTCCTCCATGT CATGCTCG GCCAGAGCA 3414 TGCTCTGG C CGAGCATG 3415 Apolipoprotein EGTGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGA 3416 Arg136CysGCACCGAGGAGCTGCGGGTG C GCCTCGCCTCCCACCTGCG gCGC-TGCCAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGCGCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTTG 3417 CGCAGGTGGGAGGCGAGGC GCACCCGCAGCTCCTCGGTGC TCTGGCCGAGCATGGGCTGCACCTCGCCGCGGTACTGCAC TGCGGGTG CGCCTCGCC 3418 GGCGAGGC G CACCCGCA 3419 Apolipoprotein ETGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGAG 3420 Arg136HisCACCGAGGAGCTGCGGGTGC G CCTCGCCTCCCACCTGCGC CGC-CACAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGCATGCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTT 3421 GCGCAGGTGGGAGGCGAGG CGCACCCGCAGCTCCTCGGTG CTCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCA GCGGGTGC GCCT CGCCT 3422 AGGCGAGG C GCACCCGC 3423 Apolipoprotein EGTGCAGTACCGCGGCGAGGTGCAGGCCATGCTCGGCCAGA 3424 Arg136SerGCACCGAGGAGCTGCGGGTG C GCCTCGCCTCCCACCTGCG gCGC-AGCCAAGCTGCGTAAGCGGCTCCTCCGCGATGCCGATGACCTGCGCAGGTCATCGGCATCGCGGAGGAGCCGCTTACGCAGCTTG 3425 CGCAGGTGGGAGGCGAGGC GCACCCGCAGCTCCTCGGTGC TCTGGCCGAGCATGGCCTGCACCTCGCCGCGGTACTGCAC TGCGGGTG CGCGTCGCC 3426 GGCGAGGC G CACCCGCA 3427 Apolipoprotein EGTGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGG 3428 Arg142CysTGCGCCTCGCCTCCCACCTG C GCAAGCTGCGTAAGCGGCTC gCGC-TGCCTCCGCGATGCCGATGACCTGCAGAAGCGCCTGGCAGTGTACACTGCCAGGCGCTTCTGCAGGTCATCGGCATCGCGGAGG 3429 AGCCGCTTACGCAGCTTGC GCAGGTGGGAGGCGAGGCGCA CCCGCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCAC CCGACCTG CGCAAGCTG 3430 CAGCTTGC G CAGGTGGG 3431 Apolipoprotein ETGCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGGT 3432 Arg142LeuGCGCCTCGCCTCCCACCTGC G CAAGCTGCGTAAGCGGCTCC CGC-CTCTCCGCGATGCCGATGACCTGCAGAAGCGCCTGGCAGTGTATACACTGCCAGGCGCTTCTGCAGCTCATCGGCATCGCGGAG 3433 GAGCCGCTACGCAGCTTG CGCAGGTGGGAGGCGAGGCGC ACCCGCAGCTCCTCGGTGCTCTGGCCGAGCATGGCCTGCA CCACCTGC GCAAGCTGC 3434 GCAGCTTG C GCAGGTGG 3435 Apolipoprotein EATGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCG 3436 Arg145CysCCTCCCACCTGCGCAAGCTG C GTAAGCGGCTCCTCCGCGAT gCGT-TGTGCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGCA 3437 TCGCGGAGGAGCCGCTTAC GCAGCTTGCGCAGGTGGGAGG CGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAGCAT GCAAGCTG CGTAAGCGG 3438 CCGCTTAC G CAGCTTGC 3439 Apolipoprotein ETGCTCGGCCAGAGCACCGAGGAGCTGGGGGTGCGCCTCGC 3440 Arg145ProCTCCCACCTGCGCAAGCTGC G TAAGCGGCTCCTCCGCGATG CGT-CCTCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCGGC 3441 ATCGCGGAGGAGCCGCTTA CGCAGCTTGCGCAGGTGGGAG GCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAGCA CAAGCTGC GTAAGCGGC 3442 GCCGCTTA C GCAGCTTG 3443 Apolipoprotein ECTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCT 3444 Lys146GlnCCCACCTGCGCAAGCTGCGT A AGCGGCTCCTCCGCGATGCC tAAG-CAGGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGGGCGCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCG 3445 GCATCGCGGAGGAGCCGCT TACGCAGCTTGCGCAGGTGGGA GGCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAG AGCTGCGT AAGCGGCTC 3446 GAGCCGCT T ACGCAGCT 3447 Apolipoprotein ECTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCT 3448 Lys146GluCCCACCTGCGCAAGCTGCGT A AGCGGCTCCTCCGCGATGCC tAAG-GAGGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCGGGGCCCCGGCCTGGTACACTGCCAGGCGCTTCTGCAGGTCATCG 3449 GCATCGCGGAGGAGCCGCT TACGCAGCTTGCGCAGGTGGGA GGCGAGGCGCACCCGCAGCTCCTCGGTGCTCTGGCCGAG AGCTGCGT AAGCGGCTC 3450 GAGCCGCT T ACGCAGCT 3451 Apolipoprotein EGCCTCCCACCTGCGCAAGCTGCGTAAGCGGCTCCTCCGCGA 3452 Arg158CysTGCCGATGACCTGCAGAAGCGCCTGGCAGTGTACCAGGCCG gCGC-TGCGGGCCCGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCCGGATGGCGCTGAGGCCGCGCTCGGCGCCCTCGCGGGCCCC 3453 GGCCTGGTACACTGCCAGGC GCTTCTGCAGGTCATCGGCAT CGCGGAGGAGCCGCTTACGCAGCTTGCGCAGGTGGGAGGC TGCAGAAG CGCCTGGCA 3454 TGCCAGGC G CTTCTGCA 3455 Apolipoprotein ECGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCCGCGAGC 3456 Gln187GluGCCTGGGGCCCCTGGTGGAA C AGGGCCGCGTGCGGGCCGC aCAG-GAGCACTGTGGGCTCCCTGGCCGGCCAGCCGCTACAGGAGCGG GCCCGCTCCTGTAGCGGCTGGCCGGCCAGGGAGCCCACAGT 3457 GGCGGCCCGCACGCGGCCCT GTTCCACCAGGGGCCCCAGG CGCTCGCGGATGGCGCTGAGGCCGCGCTCGGCGCCCTCGC G TGGTGGAAC AGGGCCGC 3458 GCGGCCCT G TTCCACCA 3459 Apolipoprotein ETGCGGGCCGCCACTGTGGGCTCCCTGGCCGGCCAGCCGCT 3460 Trp210TermACAGGAGCGGGCCCAGGCCT G GGGCGAGCGGCTGCGCGC TGG-TAGGCGGATGGAGGAGATGGGCAGCCGGACCCGCGACCGCCTG GATCCAGGCGGTCGCGGGTCCGGCTGCCCATCTCCTCCATCCG 3461 CGCGCGCAGCCGCTCGCCC CAGGCCTGGGCCCGCTCCTGT AGCGGCTGGCCGGCCAGGGAGCCCACAGTGGCGGCCCGCA CCAGGCCT GGGGCGAGC 3462 GCTCGCCC C AGGCCTGG 3463 Apolipoprotein ECAGGCCTGGGGCGAGCGGCTGCGCGCGCGGATGGAGGAGA 3464 Arg228CysTGGGCAGCCGGACCCGCGAC C GCCTGGACGAGGTGAAGGA cCGC-TGCGCAGGTGGCGGAGGTGCGCGCCAAGCTGGAGGAGCAGGCC CGGGCCTGCTCCTCCAGCTTGGCGCGCACCTCCGCCACCTGC 3465 TCCTTCACCTCGTCCAGGC GGTCGCGGGTCCGGCTGCCCAT CTCCTCCATCCGCGCGCGCAGCCGCTCGCCCCAGGCCTG CCCGCGAC CGCCTGGAC 3466 GTCCAGGC G GTCGCGGG 3467 Apolipoprotein ECGGACCCGCGACCGCCTGGACGAGGTGAAGGAGCAGGTGG 3468 Glu244LysCGGAGGTGCGCGCCAAGCTG G AGGAGCAGGCCCAGCAGAT gGAG-MGACGCCTGCAGGCCGAGGCCTTCCAGGCCCGCCTCAAGAGCTAGCTCTTGAGGCGGGCCTGGPAGGCCTCGGCCTGCAGGCGT 3469 ATCTGCTGGGCCTGCTCCT CCAGCTTGGCGCGCACCTCCGC CACCTGCTCCTTCACCTCGTCCAGGCGGTCGCGGGTCCG CCAAGCTG GAGGAGCAG 3470 CTGCTCCT C CAGCTTGG 3471

EXAMPLE 21 Familial Hypercholesterolemia—LDLR

[0143] Familial hypercholesterolemia is characterized by elevation ofserum cholesterol bound to low density lipoprotein (LDL) and is, hence,one of the conditions producing a hyperlipoproteinemia phenotype.Familial hypercholesterolemia is an autosomal dominant disordercharacterized by elevation of serum cholesterol bound to low densitylipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene cause thisdisorder. The attached table discloses the correcting oligonucleotidebase sequences for the LDLR oligonucleotides of the invention. TABLE 28LDLR Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ IDMutation Correcting Oligos NO: HypercholesterolaemiaGCGTTGAGAGACCCTTTCTCCTTTTCCTCTCTCTCAGTGGGC 3472 Glu10TermGACAGATGCGAAAGAAAC G AGTTCCAGTGCCAAGACGGGAA cGAG-TAGATGCATCTCCTACAAGTGGGTCTGCGATGGCAGCGCTGCAGCGCTGCCATCGCAGACCCACTTGTAGGAGATGCATTTCC 3473 CGTCTTGGCACTGGAACT CGTTTCTTTCGCATCTGTCGCCCA CTGAGAGAGAGGAAAAGGAGAAAGGGTCTCTCAACGC AAAGAAAC GAGTTCCAG 3474 CTGGAACT C GTTTCTTT 3475 HypercholesterolaemiaAGACCCTTTCTCCTTTTCCTCTCTCTCAGTGGGCGACAGA 3476 Gln12TermTGCGAAAGAAACGAGTTC C AGTGCCAAGACGGGAAATGCATC cCAG-TAGTCCTACAAGTGGGTCTGCGATGGCAGCGCTGAGTGCCGGCACTCAGCGCTGCCATCGCAGACCCACTTGTAGGAGATG 3477 CATTTCCCGTCTTGGCACT GGAACTCGTTTCTTTCGCATCTGT CGCCCACTGAGAGAGAGGAAAAGGAGAAAGGGTCTCT ACGAGTTC CAGTGCCAA 3478 TTGGCACT G GAACTCGT 3479 HypercholesterolaemiaCCTTTCTCCTTTTCCTCTCTCTCAGTGGGCGACAGATGCGAA 3480 Gln14TermAGAAACGAGTTCCAGTGC C AAGACGGGAAATGCATCTCCTAC cCM-TAAAAGTGGGTCTGCGATGGCAGCGCTGAGTGCCAGGATGCATCCTGGCACTCAGCGCTGCCATCGCAGACCCACTTGTAG 3481 GAGATGCATTTCCCGTCTT GGCACTGGAACTCGTTTCTTTCG CATCTGTCGCCCACTGAGAGAGAGGAAAAGGAGAAAGG TCCAGTGC CAAGACGGG 3482 CCCGTCTT G GCACTGGA 3483 HypercholesterolaemiaGCGACAGATGCGAAAGAAACGAGTTCCAGTGCCAAGACGGG 3484 Trp23TermAAATGCATCTCCTACAAGT G GGTCTGCGATGGCAGCGCTGAG TGG-TAGTGCCAGGATGGCTCTGATGAGTCCCAGGAGACGTGCTGCAGCACGTCTCCTGGGACTCATCAGAGCCATCCTGGCACTCA 3485 GCGCTGCCATCGCAGACC CACTTGTAGGAGATGCATTTCCCG TCTTGGCACTGGAACTCGTTTCTTTCGCATCTGTCGC CTACAAGT GGGTCTGCG 3486 CGCAGACC C ACTTGTAG 3487 HypercholesterolaemiaAACGAGTTCCAGTGCCAAGACGGGAAATGCATCTCCTACAAG 3488 Ala29SerTGGGTCTGCGATGGCAGC G CTGAGTGCCAGGATGGCTCTGA cGCT-TCTTGAGTCCCAGGAGACGTGCTGTGAGTCCCCTTTGGGCATGCCCAAAGGGGACTCACAGCACGTCTCCTGGGACTCATCA 3489GAGCCATCCTGGCACTCAGCGCTGCCATCGCAGACCCACTTGTAGGAGATGCATTTCCCGTCTTGGCACTGGAACTCGTT ATGGCAGC G CTGAGTGC 3490GCACTCAG C GCTGCCAT 3491 HypercholesterolaemiaTCCAGTGCCAAGACGGGAAATGCATCTCCTACAAGTGGGTCT 3492 Cys31TyrGCGATGGCAGCGCTGAGT G CCAGGATGGCTCTGATGAGTCC TGC-TACCAGGAGACGTGCTGTGAGTCCCCTTTGGGCATGATATGCATATCATGCCCAAAGGGGACTCACAGCACGTCTCCTGGGAC 3493 TCATCAGAGCCATCCTGG CACTCAGCGCTGCCATCGCAGAC CCACTTGTAGGAGATGCATTTCCCGTCTTGGCACTGGA CGCTGAGT GCCAGGATG 3494 CATCCTGG C ACTCAGCG 3495 HypercholesterolaemiaAATCCTGTCTCTTCTGTAGTGTCTGTCACCTGCAAATCCGGG 3496 Arg57CysGACTTCAGCTGTGGGGGC C GTGTCAACCGCTGCATTCCTCA cCGT-TGTGTTCTGGAGGTGCGATGGCCAAGTGGACTGCGACAACGCGTTGTCGCAGTCCACTTGGCCATCGCACCTCCAGAACTGAG 3497 GAATGCAGCGGTTGACAC GGCCCCCACAGCTGAAGTCCCCG GATTTGCAGGTGACAGACACTACAGAAGAGACAGGATT GTGGGGGC CGTGTCAAC 3498 GTTGACAC G GCCCCCAC 3499 HypercholesterolaemiaTCTGTCACCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCG 3500 Gln64TermTGTCAACCGCTGCATTCCT C AGTTCTGGAGGTGCGATGGCCA tCAG-TAGAGTGGACTGCGACAACGGCTCAGACGAGCAAGGCTGTCGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCACTTGGC 3501 CATCGCACCTCCAGAACT GAGGPATGCAGCGGTTGACACGG CCCCCACAGCTGAAGTCCCCGGATTTGCAGGTGACAGA GCATTCCT CAGTTCTGG 3502 CCAGAACT G AGGAATGC 3503 HypercholesterolaemiaACCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAA 3504 Trp66GlyCCGCTGCATTCCTCAGTTC T GGAGGTGCGATGGCCAAGTGG cTGG-GGGACTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCCA 3505 CTTGGCCATCGCACCTCC AGAACTGAGGAATGCAGCGGTTG ACACGGCCCCCACAGCTGAAGTCCCCGGATTTGCAGGT CTCAGTTC TGGAGGTGC 3506 GCACCTCC A GAACTGAG 3507 HypercholesterolaemiaCCTGCAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAAC 3508 Trp66TermCGCTGCATTCCTCAGTTCT G GAGGTGCGATGGCCAAGTGGA TGG-TAGCTGCGACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGCACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGCAGTCC 3509 ACTTGGCCATCGCACCTC CAGAACTGAGGAATGCAGCGGTTG ACACGGCCCCCACAGCTGAAGTCCCCGGATTTGCAGG TCAGTTCT GGAGGTGCG 3510 CGCACCTC C AGAACTGA 3511 HypercholesterolaemiaAAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTG 3512 Cys68ArgCATTCCTCAGTTCTGGAGG T GCGATGGCCAAGTGGACTGCGA gTGC-CGCCAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTCGC 3513 AGTCCACTTGGCCATCGC ACCTCCAGAACTGAGGAATGCAG CGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGATTT TCTGGAGG TGCGATGGC 3514 GCCATCGC A CCTCCAGA 3515 HypercholesterolaemiaATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCA 3516 Cys68TrpTTCCTCAGTTCTGGAGGTG C GATGGCCAAGTGGACTGCGACA TGCg-TGGACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTC 3517 GCAGTCCACTTGGCCATC GCACCTCCAGAACTGAGGAATGCA GCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGAT TGGAGGTG CGATGGCCA 3518 TGGCCATC G CACCTCCA 3519 HypercholesterolaemiaAATCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGC 3520 Cys68TyrATTCCTCAGTTCTGGAGGT G CGATGGCCAAGTGGACTGCGAC TGC-TACAACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGTC 3521 GCAGTCCACTTGGCCATCG CACCTCCAGAACTGAGGAATGCA GCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGATT CTGGAGGT GCGATGGCC 3522 GGCCATCG C ACCTCCAG 3523 HypercholesterolaemiaTCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCAT 3524 Asp69AsnTCCTCAGTTCTGGAGGTGC G ATGGCCAAGTGGACTGCGACA cGAT-AATACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGT 3525 CGCAGTCCACTTGGCCAT CGCACCTCCAGAACTGAGGAATG CAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGA GGAGGTGC GATGGCCAA 3526 TTGGCCAT C GCACCTCC 3527 HypercholesterolaemiaCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATT 3528 Asp69GlyCCTCAGTTCTGGAGGTGC G ATGGCCAAGTGGACTGCGACAA GAT-GGTCGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGCGCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTT 3529 GTCGCAGTCCACTTGGCCA TCGCACCTCCAGPACTGAGGAAT GCAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGG GAGGTGCG ATGGCCAAG 3530 CTTGGCCA T CGCACCTC 3531 HypercholesterolaemiaTCCGGGGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCAT 3532 Asp69TyrTCCTCAGTTCTGGAGGTGC G ATGGCCAAGTGGACTGCGACA cGAT-TATACGGCTCAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAGCCGTTGT 3533 CGCAGTCCACTTGGCCAT CGCACCTCCAGAACTGAGGAATG CAGCGGTTGACACGGCCCCCACAGCTGAAGTCCCCGGA GGAGGTGC GATGGCCAA 3534 TTGGCCAT C GCACCTCC 3535 HypercholesterolaemiaGACTTCAGCTGTGGGGGCCGTGTCAACCGCTGCATTCCTCA 3536 Gln71GluGTTCTGGAGGTGCGATGGC C AAGTGGACTGCGACAACGGCT cCAA-GAACAGACGAGCAAGGCTGTCGTAAGTGTGGCCCTGCCTTTGCAAAGGCAGGGCCACACTTACGACAGCCTTGCTCGTCTGAG 3537 CCGTTGTCGCAGTCCACTT GGCCATCGCACCTCCAGAACTGA GGAATGCAGCGGTTGACACGGCCCCCACAGCTGAAGTC GCGATGGC CAAGTGGAC 3538 GTCCACTT G GCCATCGC 3539 HypercholesterolaemiaTGTGGGGGCCGTGTCAACCGCTGCATTCCTCAGTTCTGGAG 3540 Cys74GlyGTGCGATGGCCAAGTGGACT G CGACAACGGCTCAGACGAGC cTGC-GGCAAGGCTGTCGTAAGTGTGGCCCTGCCTTTGCTATTGAGCGCTCAATAGCAAAGGCAGGGCCACACTTACGACAGCCTTGCT 3541 CGTCTGAGCCGTTGTCGC AGTCCACTTGGCCATCGCACCTC CAGAACTGAGGAATGCAGCGGTTGACACGGCCCCCACA AAGTGGAC TGCGACAAC 3542 GTTGTCGC A GTCCACTT 3543 HypercholesterolaemiaTCAACCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAG 3544 Ser78TermTGGACTGCGACAACGGCT C AGACGAGCAAGGCTGTCGTAAG TCA-TGATGTGGCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCTAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCACACTTA 3545 CGACAGCCTTGCTCGTCT GAGCCGTTGTCGCAGTCCACTTGG CCATCGCACCTCCAGAACTGAGGAATGCAGCGGTTGA CAACGGCT CAGACGAGC 3546 GCTCGTCT G AGCCGTTG 3547 HypercholesterolaemiaCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA 3548 Glu80LysCTGCGACAACGGCTCAGAC G AGCAAGGCTGTCGTAAGTGTG cGAG-AAGGCGCTGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGATCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCA 3549 CACTTACGACAGCCTTGCT CGTCTGAGCCGTTGTCGCAGTCC ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCG GCTCAGAC GAGCAAGGC 3550 GCCTTGCT C GTCTGAGC 3551 HypercholesterolaemiaCGCTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGA 3552 Glu80TermCTGCGACAACGGCTCAGAC G AGCAAGGCTGTCGTAAGTGTG cGAG-TAGGCCCTGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGATCCGCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGGCCA 3553 CACTTACGACAGCCTTGCT CGTCTGAGCCGTTGTCGCAGTCC ACTTGGCCATCGCACCTCCAGAACTGAGGAATGCAGCG GCTCAGAC GAGCAAGGC 3554 HypercholesterolaemiaTGCATTCCTCAGTTCTGGAGGTGCGATGGCCAAGTGGACTGC 3556 Gln81TermGACAACGGCTCAGACGAG C AAGGCTGTCGTAAGTGTGGCCC gCAA-TAATGCCTTTGCTATTGAGCCTATCTGAGTCCTGGGGAGTGCACTCCCCAGGACTCAGATAGGCTCAATAGCAAAGGCAGGG 3557 CCACACTTACGACAGCCTT GCTCGTCTGAGCCGTTGTCGCAG TCCACTTGGCCATCGCACCTCCAGAACTGAGGAATGCA CAGACGAG CAAGGCTGT 3558 ACAGCCTT G CTCGTCTG 3559 HypercholesterolaemiaTGGGAGACTTCACACGGTGATGGTGGTCTCGGCCCATCCAT 3560 Cys88ArgCCCTGCAGCCCCCAAGACG T GCTCCCAGGACGAGTTTCGCT gTGC-CGCGCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTCTGTGCACAGACGAACTGCCGAGAGATGCACTTCCCATCGTGGCAG 3561 CGAAACTCGTCCTGGGAGC ACGTCTTGGGGGCTGCAGGGAT GGATGGGCCGAGACCACCATCACCGTGTGAAGTCTCCCA CCAAGACG TGCTCCCAG 3562 CTGGGAGC A CGTCTTGG 3563 HypercholesterolaemiaCACGTGATGGTGGTCTCGGCCCATCCATCCCTGCAGCCCC 3564 Glu92TermCAAGACGTGCTCCCAGGACGAGTTTCGCTGCCACGATGGGA cGAG-TAGAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGCCCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTTC 3565 CCATCGTGGCAGCGAAACT CGTCCTGGGAGCACGTCTTGGG GGCTGCAGGGATGGATGGGCCGAGACCACCATCACCGTG CCCAGGAC GAGTTTCGC 3566 GCGAAACT C GTCCTGGG 3567 HypercholesterolaemiaGGTGGTCTCGGCCCATCCATCCCTGCAGCCCCCAAGACGTG 3568 Cys95ArgCTCCCAGGACGAGTTTCGC T GCCACGATGGGAAGTGCATCT cTGC-CGCCTCGGCAGTTCGTCTGTGACTCAGACCGGGACTGCTTGGCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGCCGAGAG 3569 ATGCACTTCCCATCGTGGC AGCGAAACTCGTCCTGGGAGCA CGTCTTGGGGGCTGCAGGGATGGATGGGCCGAGACCACC AGTTTCGC TGCCACGAT 3570 ATCGTGGC A GCGAAACT 3571 HypercholesterolaemiaCTCGGCCCATCCATCCCTGCAGCCCCCAAGACGTGCTCCCA 3572 Asp97TyrGGACGAGTTTCGCTGCCAC G ATGGGAAGTGCATCTCTCGGC cGAT-TATAGTTCGTCTGTGACTCAGACCGGGACTGCFGGACGGCTAGCCGTCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGC 3573 CGAGAGATGCACTTCCCAT CGTGGCAGCGAAACTCGTCCTG GGAGCACGTCTTGGGGGCTGCAGGGATGGATGGGCCGAG GCTGCCAC GATGGGAAG 3574 CTTCCCAT C GTGGCAGC 3575 HypercholesterolaemiaGGGTCGGGACACTGCCTGGCAGAGGCTGCGAGCATGGGGC 3576 Trp(-12)ArgCCTGGGGCTGGPAATTGCGC T GGACCGTCGCCTTGCTCCTC cTGG-AGGGCCGCGGCGGGGACTGCAGGTAAGGCTTGCTCCAGGCGCCGGCGCCTGGAGCAAGCCTTACCTGCAGTCCCCGCCGCGGC 3577 GAGGAGCAAGGCGACGGTCC AGCGCAATTTCCAGCCCCAGG GCCCCATGCTCGCAGCCTCTGCCAGGCAGTGTCCCGACCC AATTGCGC TGGACCGTC 3578 GACGGTCC A GCGCAATT 3579 HypercholesterolaemiaCAGCAGGTCGTGATCCGGGTCGGGACACTGCCTGGCAGAGG 3580 Trp(-18)TermCTGCGAGCATGGGGCCCTG G GGCTGGAAATTGCGCTGGACC TGGg-TGAGTCGCCTTGCTCCTCGCCGCGGCGGGGACTGCAGGTAAGCTTACCTGCAGTCCCCGCCGCGGCGAGGAGCAAGGCGACG 3581 GTCCAGCGCAATTTCCAGCC CCAGGGCCCCATGCTCGCAGC CTCTGCCAGGCAGTGTCCCGACCCGGATCACGACCTGCTG GGGCCCTG GGGCTGGAA 3582 TTCCAGCC C CAGGGCCC 3583 HypercholesterolaemiaCAGCTAGGACACAGCAGGTCGTGATCCGGGTCGGGACACTG 3584 Met(-21)LeuCCTGGCAGAGGCTGCGAGC A TGGGGCCCTGGGGCTGGAAA cATG-TTGTTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGATCCCCGCCGCGGCGAGGAGCAAGGCGACGGTCCAGCGCAA 3585 TTTCCAGCCCCAGGGCCCCA TGCTCGCAGCCTCTGCCAGGC AGTGTCCCGACCCGGATCACGACCTGCTGTGTCCTAGCTG CTGCGAGC ATGGGGCCC 3586 GGGCCCCA T GCTCGCAG 3587 HypercholesterolaemiaCAGCTAGGACACAGCAGGTCGTGATCCGGGTCGGGACACTG 3588 Met(-21)ValCCTGGCAGAGGCTGCGAGC A TGGGGCCCTGGGGCTGGAAA cATG-GTGTTGCGCTGGACCGTCGCCTTGCTCCTCGCCGCGGCGGGGATCCCCGCCGCCGCGAGCAGCAAGCCCACCGTCCAGCGCAA 3589 TTTCCAGCCCCAGGGCCCCA TGCTCGCAGCCTCTGCCAGGC AGTGTCCCGACCCCCATCACCACCTCCTCTCTCCTAGCTG CTGCGAGC ATGGGGCCC 3590 GGGCCCCA T GCTCGCAG 3591 HypercholesteroiaemiaATCCCTGCAGCCCCCAAGACGTGCTCCCAGGACGAGTTTCG 3592 Ile101PheCTGCCACGATGGGAAGTGC A TCTCTCGGCAGTTCGTCTGTGA cATC-TTCCTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGCCTAGGCCTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCA 3593 CAGACGAACTGCCGAGAGA TGCACTTCCCATCGTGGCAGCG AAACTCGTCCTGGGAGCACGTCTTGGGGGCTGCAGGGAT GGAAGTGC ATCTCTCGG 3594 CCGAGAGA T GCACTTCC 3595 HypercholesterolaemiaGCCCCCAAGACGTGCTCCCAGGACGAGTTTCGCTGCCACGA 3596 Gln104TermTGGGAAGTGCATCTCTCGG C AGTTCGTCTGTGACTCAGACCG gCAG-TAGGGACTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGGCCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCAGTCCCG 3597 GTCTGAGTCACAGACGAACT GCCGAGAGATGCACTTCCCATC GTGGCAGCGAAACTCGTCCTGGGAGCACGTCTTGGGGGC TCTCTCGG CAGTTCGTC 3598 GACGAACT G CCGAGAGA 3599 HypercholesterolaemiaTTTCGCTGCCACGATGGGAAGTGCATCTCTCGGCAGTTCGTC 3600 Cys113ArgTGTGACTCAGACCGGGAC T GCTTGGACGGCTCAGACGAGGC cTGC-CGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTCCGGAAGCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGC 3601 CTCGTCTGAGCCGTCCAAGC AGTCCCGGTCTGAGTCACAGA CGAACTGCCGAGAGATGCACTTCCCATCGTGGCAGCGAAA ACCGGGAC TGCTTGGAC 3602 GTCCAAGC A GTCCCGGT 3603 HypercholesterolaemiaAAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGAC 3604 Glu119LysTGCTTGGACGGCTCAGAC G AGGCCTCCTGCCCGGTGCTCAC cGAG-AAGCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGGTG 3605 AGCACCGGGCAGGAGGCCT CGTCTGAGCCGTCCAAGCAGTC CCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTT GCTCAGAC GAGGCCTCC 3606 GGAGGCCT C GTCTGAGC 3607 HypercholesterolaemiaAAGTGCATCTCTCGGCAGTTCGTCTGTGACTCAGACCGGGAC 36O8 Glu119TermTGCTTGGACGGCTCAGAC G AGGCCTCCTGCCCGGTGCTCAC cGAG-TAGCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAGGTG 3609 AGCACCGGGCAGGAGGCCT CGTCTGAGCCGTCCAAGCAGTC CCGGTCTGAGTCACAGACGAACTGCCGAGAGATGCACTT GGTCAGAC GAGGCCTCC 3610 GGAGGCCT C GTCTGAGC 3611 HypercholesterolaemiaTCGGCAGTTCGTCTGTGACTCAGACCGGGACTGCTTGGACG 3612 Cys122TermGCTCAGACGAGGCCTCCTG C CCGGTGCTCACCTGTGGTCCC TGCc-TGAGCCAGCTTCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAAGCTGGCGG 3613 GACCACAGGTGAGCACCGG GCAGGAGGCCTCGTCTGAGCC GTCCAAGCAGTCCCGGTCTGAGTCACAGACGAACTGCCGA GCCTCCTG CCCGGTGCT 3614 AGCACCGG G CAGGAGGC 3615 HypercholesterolaemiaTGACTCAGACCGGGACTGCTTGGACGGCTCAGACGAGGCCT 3616 Cys127TrpCCTGCCCGGTGCTCACCTG T GGTCCCGCCAGCTTCCAGTGC TGTg-TGGAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGACGTCGCAGGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGC 3617 ACTGGAAGCTGGCGGGACC ACAGGTGAGCACCGGGCAGGA GGCCTCGTCTGAGCCGTCCAAGCAGTCCCGGTCTGAGTCA CTCACCTG TGGTCCCGC 3618 GCGGGACC A CAGGTGAG 3619 HypercholesterolaemiaTGCTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCAC 3620 Gln133TermCTGTGGTCCCGCCAGCTTC C AGTGCAACAGCTCCACCTGCAT CCAG-TAGCCCCCAGCTGTGGGCGTGCGACAACGACCCCGACTGCGCGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGGAT 3621 GCAGGTGGAGCTGTTGCACT GGAAGCTGGCGGGACCACAGG TGAGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAAGCA CCAGCTTC CAGTGCAAC 3622 GTTGCACT G GAAGCTGG 3623 HypercholesterolaemiaTTGGACGGCTCAGACGAGGCCTCCTGCCCGGTGCTCACCTG 3624 Cys134GlyTGGTCCCGCCAGCTTCCAG T GCAACAGCTCCACCTGCATCC gTGC-GGCCCCAGCTGTGGGCCTGCGACAACGACCCCGACTGCGAAGCTTCGCAGTCGGGGTCGTTGTCGCAGGCCCACAGCTGGGGG 3625 ATGCAGGTGGAGCTGTTGC ACTGGAAGCTGGCGGGACCACA GGTGAGCACCGGGCAGGAGGCCTCGTCTGAGCCGTCCAA GCTTCCAG TGCAACAGC 3626 GCTGTTGC A CTGGAAGC 3627 HypercholesterolaemiaGAGGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTT 3628 Cys139GlyCCAGTGCAACAGCTCCACC T GCATCCCCCAGCTGTGGGCCT cTGC-GGCGCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGTACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCAG 3629 GCCCACAGCTGGGGGATGC AGGTGGAGCTGTTGCACTGGAA GCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGCCTC GCTCCACC TGCATCCCC 3630 GGGGATGC A GGTGGAGC 3631 HypercholesterolaemiaAGGCCTCCTGCCCGGTGCTCACCTGTGGTCCCGCCAGCTTC 3632 Cys139TyrCAGTGCAACAGCTCCACCT G CATCCCCCAGCTGTGGGCCTG TGC-TACCGACAACGACCCCGACTGCGAAGATGGCTCGGATGAGTGCACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTGTCGCA 3633 GGCCCACAGCTGGGGGATG CAGGTGGAGCTGTTGCACTGGA AGCTGGCGGGACCACAGGTGAGCACCGGGCAGGAGGCCT CTCCACCT GCATCCCCC 3634 GGGGGATG C AGGTGGAG 3635 HypercholesterolaemiaCTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCAT 3636 Cys146TermCCCCCAGCTGTGGGCCTG C GACAACGACCCCGACTGCGAAG TGCg-TGAATGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTTC 3637 GCAGTCGGGGTCGTTGTC GCAGGCCCACAGCTGGGGGATG CAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACAG TGGGCCTG CGACAACGA 3638 TCGTTGTC G CAGGCCCA 3639 HypercholesterolaemiaTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC 3640 Asp147AsnCCCCAGCTGTGGGCCTGC G ACAACGACCCCGACTGCGAAGA cGAC-AACTGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTAAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT 3641 CGCAGTCGGGGTCGTTGT CGCAGGCCCACAGCTGGGGGAT GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA GGGCCTGC GACAACGAC 3642 GTCGTTGT C GCAGGCCC 3643 HypercholesterolaemiaTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC 3644 Asp147HisCCCCAGCTGTGGGCCTGC G ACAACGACCCCGACTGCGAAGA cGAC-CACTGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTAAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT 3645 CGCAGTCGGGGTCGTTGT CGCAGGCCCACAGCTGGGGGAT GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA GGGCCTGC GACAACGAC 3646 GTCGTTGT C GCAGGCCC 3647 HypecholesterolaemiaTGTGGTCCCGCCAGCTTCCAGTGCAACAGCTCCACCTGCATC 3648 Asp147TyrCCCCAGCTGTGGGCCTGC G ACAACGACCCCGACTGCGAAGA cGAC-TACTGGCTCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTAAAGACCCCTACAGCGCTGCGGCCACTCATCCGAGCCATCTT 3649 CGCAGTCGGGGTCGTTGT CGCAGGCCCACAGCTGGGGGAT GCAGGTGGAGCTGTTGCACTGGAAGCTGGCGGGACCACA GGGCCTGC GACAACGAC 3650 GTCGTTGT C GCAGGCCC 3651 HypercholesterolaemiaTTCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGC 3652 Cys152ArgCTGCGACAACGACCCCGAC T GCGAAGATGGCTCGGATGAGT cTGC-CGCGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCCAC 3653 TCATCCGAGCCATCTTCGC AGTCGGGGTCGTTGTCGCAGGC CCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA ACCCCGAC TGCGAAGAT 3654 ATCTTCGC A GTCGGGGT 3655 HypercholesterolaemiaTTCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGC 3656 Cys152GlyCTGCGACAACGACCCCGAC T GCGAAGATGGCTCGGATGAGT cTGC-GGCGGCCGGAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCCAC 3657 TCATCCGAGCCATCTTCGC AGTCGGGGTCGTTGTCGCAGGC CCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGGAA ACCCCGAC TGCGAAGAT 3658 ATCTTCGC A GTCGGGGT 3659 HypercholesterolaemiaCCAGTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCT 3660 Cys152TrpGCGACAACGACCCCGACTG C GAAGATGGCTCGGATGAGTGG TGCg-TGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGACGTCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCGGCC 3661 ACTCATCCGAGCCATCTTC GCAGTCGGGGTCGTTGTCGCAG GCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCACTGG CCCGACTG CGAAGATGG 3662 CCATCTTC G CAGTCGGG 3663 HypercholesterolaemiaTGCAACAGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGA 3664 Asp154AsnCAACGACCCCGACTGCGAA G ATGGCTCGGATGAGTGGCCGC aGAT-AATAGCGCTGTAGGGGTCTTTACGTGTTCCAAGGGGACAGTATACTGTCCCCTTGGAACACGTAAAGACCCCTACAGCGCTGCG 3665 GCCACTCATCCGAGCCAT CTTCGCAGTCGGGGTCGTTGTCG CAGGCCCACAGCTGGGGGATGCAGGTGGAGCTGTTGCA ACTGCGAA GATGGCTCG 3666 CGAGCCAT C TTCGCAGT 3667 HypercholesterolaemiaGCTCCACCTGCATCCCCCAGCTGTGGGCCTGCGACAACGAC 3668 Ser156LeuCCCGACTGCGAAGATGGC T CGGATGAGTGGCCGCAGCGCTG TCG-TTGTAGGGGTCTTTACGTGFTTCCAAGGGGACAGTAGCCCCTGCAGGGGCTACTGTCCCCTTGGAACACGTAAAGACCCCTACAG 3669 CGCTGCGGCCACTCATCC GAGCCATCTTCGCAGTCGGGGTC GTTGTCGCAGGCCCACAGCTGGGGGATGCAGGTGGAGC AGATGGCT CGGATGAGT 3670 ACTCATCC G AGCCATCT 3671 HypercholesterolaemiaTGTGGGCCTGCGACAACGACCCCGACTGCGAAGATGGCTCG 3672 Cys163TyrGATGAGTGGCCGCAGCGCT G TAGGGGTCTTTACGTTCCAA TGT-TATGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTGCAGTGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTG 3673 GAACACGTAAAGACCCCTA CAGCGCTGCGGCCACTCATCCG AGCCATCTTCGCAGTCGGGGTCGTTGTCGCAGGCCCACA GCAGCGCT GTAGGGGTC 3674 GACCCCTA C AGCGCTGC 3675 HypercholesterolaemiaCACGACCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGC 3676 Tyr167TermAGCGCTGTAGGGGTCTTTA C GTGTTCCAAGGGGACAGTAGC TACg-TAGCCCTGCTCGGCCTTCGAGTTCCACTGCCTAAGTGGCGAGCTCGCCACTTAGGCAGTGGAACTCGAAGGCCGAGCAGGGGC 3677 TACTGTCCCCTTGGAACAC GTAAAGACCCCTACAGCGCTGCG GCCACTCATCCGAGCCATCTTCGCAGTCGGGGTCGTTG GGTCTTTA CGTGTTCCA 3678 TGGAACAC G TAAAGACC 3679 HypercholesterolaemiaCCCGACTGCGAAGATGGCTCGGATGAGTGGCCGCAGCGCTG 3680 Gln170TermTAGGGGTCTTTACGTGTTC C AAGGGGACAGTAGCCCCTGCTC cCM-TAAGGCCTTCGAGTTCCACTGCCTAAGTGGCGAGTGCATCCGGATGCACTCGCCACTTAGGCAGTGGAACTCGAAGGCCGAG 3681 CAGGGGCTACTGTCCCCTT GGAACACGTAAAGACCCCTACAG CGCTGCGGCCACTCATCCGAGCCATCTTCGCAGTCGGG ACGTGTTC CAAGGGGAC 3682 GTCCCCTT G GAACACGT 3683 HyperchoiesterolaemiaCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTC 3684 Cys176PheCAAGGGGACAGTAGCCCCT G CTCGGCCTTCGAGTTCCACTG TGC-TTCCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA 3685 GTGGAACTCGAAGGCCGAG CAGGGGCTACTGTCCCCTTGGA ACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG TAGCCCCT GCTCGGCCT 3686 AGGCCGAG C AGGGGCTA 3687 HypercholesterolaemiaCGGATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTC 3688 Cys176TyrCAAGGGGACAGTAGCCCCT G CTCGGCCTTCGAGTTCCACTG TGC-TACCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA 3689 GTGGAACTCGAAGGCCGAG CAGGGGCTACTGTCCCCTTGGA ACACGTAAAGACCCCTACAGCGCTGCGGCCACTCATCCG TAGCCCCT GCTCGGCCT 3690 AGGCCGAG C AGGGGCTA 3691 HypercholesterolaemiaATGAGTGGCCGCAGCGCTGTAGGGGTCTTTACGTGTTCCAAG 3692 Ser177LeuGGGACAGTAGCCCCTGCT C GGCCTTCGAGTTCCACTGCCTA TCG-TTGAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATGGCCATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAG 3693 GCAGTGGAACTCGAAGGCC GAGCAGGGGCTACTGTCCCCTT GGAACACGTAAAGACCCCTACAGCGCTGCGGCCACTCAT CCCCTGCT CGGCCTTCG 3694 CGAAGGCC G AGCAGGGG 3695 HypercholesterolaemiaTACGTGTTCCAAGGGGACAGTAGCCCCTGCTCGGCCTTCGA 3696 Glu187LysGTTCCACTGCCTAAGTGGC G AGTGCATCCACTCCAGCTGGC cGAC-AAGGCTGTGATGGTGGCCCCGACTGCAAGGACAAATCTGACGCGTCAGATTTGTCCTTGCAGTCGGGGCCACCATCACAGCGC 3697 CAGCTGGAGTGGATGCACT CGCCACTTAGGCAGTGGAACTC GAAGGCCGAGCAGGGGCTACTGTCCCCTTGGAACACGTA TAAGTGGC GAGTGCATC 3698 GATGCACT C GCCACTTA 3699 HypercholesterolaemiaCAAGGGGACAGTAGCCCCTGCTCGGCCTTCGAGTTCCACTG 3700 His190TyrCCTAAGTGGCGAGTGCATC C ACTCCAGCTGGCGCTGTGATG cCAC-TACGTGGCCCCGACTGCAAGGACAAATCTGACGAGGAAAACTAGTTTTCCTCGTCAGATTTGTCCTTGCAGTCGGGGCCACCAT 3701 CACAGCGCCAGCTGGAGT GGATGCACTCGCCACTTAGGCAG TGGAACTCGAAGGCCGAGCAGGGGCTACTGTCCCCTTG AGTGCATC CACTCCAGC 3702 GCTGGAGT G GATGCACT 3703 HypercholesterolaemiaCCTTCGAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCA 3704 Gly198AspGCTGGCGCTGTGATGGTG G CCCCGACTGCAAGGACAAATCTGGCGACGACGAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCGTCAGAT 3705 TTGTCCTTGCAGTCGGGG CCACCATCACAGCGCCAGCTGGA GTGGATGCACTCGCCACTTAGGCAGTGGAACTCGAAGG TGATGGTG GCCCCGACT 3706 AGTCGGGG C CACCATCA 3707 HypercholesterolaemiaGAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTG 3708 Asp200AsnGCGCTGTGATGGTGGCCCC G ACTGCAAGGACAAATGTGACG cGAC-AACAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCG 3709 TCAGATTTGTCCTTGCAGT CGGGGCCACCATCACAGCGCCAG CTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC GTGGCCCC GACTGCAAG 3710 CTTGCAGT C GGGGCCAC 3711 HypercholesterolaemiaAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGC 3712 Asp200GlyGCTGTGATGGTGGCCCCG A CTGCAAGGACAAATCTGACGAG GAC-GGCGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTC 3713 GTCAGATTTGTCCTTGCAG TCGGGGCCACCATCACAGCGCCA GCTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACT TGGCCCCG ACTGCAAGG 3714 CCTTGCAG T CGGGGCCA 3715 HypercholesterolaemiaGAGTTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTG 3716 Asp200TyrGCGCTGTGATGGTGGCCCC G ACTGCAAGGACAAATCTGACG cGAC-TACAGGAAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTCCTCG 3717 TCAGATTTGTCCTTGCAGT CGGGGCCACCATCACAGCGCCAG CTGGAGTGGATGCACTCGCCACTTAGGCAGTGGAACTC GTGGCCCC GACTGCAAG 3718 CTTGCAGT C GGGGCCAC 3719 HypercholesterolaemiaCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCT 3720 Cys201TermGTGATGGTGGCCCCGACTG C AAGGACAAATCTGACGAGGAA TGCa-TGAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTT 3721 CCTCGTCAGATTTGTCCTT GCAGTCGGGGCCACCATCACAGC GCCAGCTGGAGTGGATGCACTCGCCACTTAGGCAGTGG CCCGACTG CAAGGACAA 3722 TTGTCCTT G CAGTCGGG 3723 HypercholesterolaemiaTCCACTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGC 3724 Cys201TyrTGTGATGGTGGCCCCGACT G CAAGGACAAATCTGACGAGGA TGC-TACAAACTGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGCGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCAGTTTTC 3725 CTCGTCAGATTTGTCCTTG CAGTCGGGGCCACCATCACAGCG CCAGCTGGAGTGGATGCACTCGCGACTTAGGCAGTGGA CCCCGACT GCAAGGACA 3726 TGTCCTTG C AGTCGGGG 3727 HypercholesterolaemiaTGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGA 3728 Asp203AsnTGGTGGCCCCGACTGCAAG G ACAAATCTGACGAGGAAAACT gGAC-AACGCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA 3729 GTTTTCCTCGTCAGATTTGT CCTTGCAGTCGGGGCCACCATC ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGCA ACTGCAAG GACAAATCT 3730 AGATTTGT C CTTGCAGT 3731 HypercholesterolaemiaGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGAT 3732 Asp203GlyGGTGGCCCCGACTGCAAGG A CAAATCTGACGAGGAAAACTG GAC-GGCCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTATATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA 3733 GTTTTCCTCGTCAGATTTG TCCTTGCAGTCGGGGCCACCATC ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGC CTGCAAGG ACAAATCTG 3734 CAGATTTG T CCTTGCAG 3735 HypercholesterolaemiaGCCTAAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGAT 3736 Asp203ValGGTGGCCCCGACTGCAAGG A CAAATCTGACGAGGAAAACTG GAC-GTCCGGTATGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTATATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATACCGCA 3737 GTTTTCCTCGTCAGATTTG TCCTTGCAGTCGGGGCCACCATC ACAGCGCCAGCTGGAGTGGATGCACTCGCCACTTAGGC CTGCAAGG ACAAATCTG 3738 CAGATTTG T CCTTGCAG 3739 HypercholesterolaemiaAGTGGCGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGG 3740 Ser205ProCCCCGACTGCAAGGACAAA T CTGACGAGGAAAACTGCGGTAT aTCT-CCTGGGCGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCCGCCCATA 3741 CCGCAGTTTTCCTCGTCAG ATTTGTCCTTGCAGTCGGGGCCA CCATCACAGCGCCAGCTGGAGTGGATGCACTCGCCACT AGGACAAA TCTGACGAG 3742 CTCGTCAG A TTTGTCCT 3743 HypercholesterolaemiaCGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCG 3744 Asp206GluACTGCAAGGACAAATCTGA C GAGGAAAACTGCGGTATGGGC GACg-GAGGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCCG 3745 CCCATACCGCAGTTTTCCTC GTCAGATTTGTCCTTGCAGTCG GGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTCG AAATCTGA CGAGGAAAA 3746 TTTTCCTC G TCAGATTT 3747 HypercholesterolaemiaGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA 3748 Glu207GlnCTGCAAGGACAAATCTGAC G AGGAAAACTGCGGTATGGGCG cGAG-CAGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCTAGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC 3749 GCCCATACCGCAGTTTTCCT CGTCAGATTTGTCCTTGCAGTC GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC AATCTGAC GAGGAAAAC 3750 GTTTTCCT C GTCAGATT 3751 HypercholesterolaemiaGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA 3752 Glu207LysCTGCAAGGACAAATCTGAC G AGGAAAACTGCGGTATGGGCG cGAG-AAGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCTAGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC 3753 GCCCATACCGCAGTTTTCCT CGTCAGATTTGTCCTTGCAGTC GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC AATGTGAC GAGGAAAAC 3754 GTTTTCCT C GTCAGATT 3755 HypercholesterolaemiaGAGTGCATCCACTCCAGCTGGCGCTGTGATGGTGGCCCCGA 3756 Glu207TermCTGCAAGGACAAATCTGAC G AGGAAAACTGCGGTATGGGCG cGAG-TAGGGGCCAGGGTGGGGGCGGGGCGTCCTATCACCTGTCCCTAGGGACAGGTGATAGGACGCCCCGCCCCCACCCTGGCCCC 3757 GCCCATACCGCAGTTTTCCT CGTCAGATTTGTCCTTGCAGTC GGGGCCACCATCACAGCGCCAGCTGGAGTGGATGCACTC AATCTGAC GAGGAAAAC 3758 GTTTTCCT C GTCAGATT 3759 HypercholesterolaemiaTCTTGAGAAAATCAACACACTCTGTCCTGTTTTCCAGCTGTGG 3760 Glu219LysCCACCTGTCGCCCTGAC G AATTCCAGTGCTCTGATGGAAACT cGAA-AAAGCATCCATGGCAGCCGGCAGTGTGACCGGGAATATGCATATTCCCGGTCACACTGCCGGCTGCCATGGATGCAGTTTC 3761 CATCAGAGCACTGGAATT CGTCAGGGCGACAGGTGGCCACA GCTGGAAAACAGGACAGAGTGTGTTGATTTTCTCAAGA GCCCTGAC GAATTCCAG 3762 CTGGAATT C GTCAGGGC 3763 HypercholesterolaemiaGAAAATCAACACACTCTGTCCTGTTTTCCAGCTGTGGCCACCT 3764 Gln221TermGTCGCCCTGACGAATTC C AGTGCTCTGATGGAAACTGCATCC cCAG-TAGATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCATGCAGTCATATTCCCGGTCACACTGCCGGCTGCCATGGATGC 3765 AGTTTCCATCAGAGCACT GGAATTCGTCAGGGCGACAGGTGG CCACAGCTGGAAAACAGGACAGAGTGTGTTGATTTTC ACGAATTC CAGTGCTCT 3766 AGAGCACT G GAATTCGT 3767 HypercholesterolaemiaCCTGTTTTCCAGCTGTGGCCACCTGTCGCCCTGACGAATTCC 3768 Cys227PheAGTGCTCTGATGGAAACT G CATCCATGGCAGCCGGCAGTGT TGC-TTCGACCGGGAATATGACTGCAAGGACATGAGCGATGAAGTACTTCATCGCTCATGTCCTTGCAGTCATATTCCCGGTCACACT 3769 GCCGGCTGCCATGGATG CAGTTTCCATCAGAGCACTGGAATT CGTCAGGGCGACAGGTGGCCACAGCTGGAAAACAGG TGGAAACT GCATCCATG 3770 CATGGATG C AGTTTCCA 3771 HypercholesterolaemiaTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCCA 3772 Asp235GluTGGCAGCCGGCAGTGTGA C CGGGAATATGACTGCAAGGACA GACc-GAATGAGCGATGMGTTGGGTGCGTTAATGGTGAGCGCTGGCCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCATGTC 3773 CTTGCAGTCATATTCCCG GTCACACTGCCGGCTGCCATGGAT GCAGTTTCCATCAGAGCACTGGAATTCGTCAGGGCGA CAGTGTGA CCGGGAATA 3774 TATTCCCG G TCACACTG 3775 HypercholesterolaemiaGTCGCCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCC 3776 Asp235GlyATGGCAGCCGGCAGTGTGA C CGGGAATATGACTGCAAGGAC GAC-GGCATGAGCGATGAAGTTGGCTGCGTTAATGGTGAGCGCTGCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCATGTCC 3777 TTGCAGTCATATTCCCGG TCACACTGCCGGCTGCCATGGATG CAGTTTCCATCAGAGCACTGGAATTCGTCAGGGCGAC GCAGTGTG ACCGGGAAT 3778 ATTCCCGG T CACACTGC 3779 HypercholesterolaemiaCCTGACGAATTCCAGTGCTCTGATGGAAACTGCATCCATGGC 3780 Glu237LysAGCCGGCAGTGTGACCGG G AATATGACTGCAAGGACATGAG gGAA-AAACGATGAAGTTGGCTGCGTTAATGGTGAGCGCTGGCCATATGGCCAGCGCTCACCATTAACGCAGCCAACTTCATCGCTCA 3781 TGTCCTTGCAGTCATATT CCCGGTCACACTGCCGGCTGCCAT GGATGCAGTTTCCATCAGAGCACTGGAATTCGTCAGG GTGACCGG GAATATGAC 3782 GTCATATT C CCGGTCAC 3783 HypercholesterolaemiaTCCAGTGCTCTGATGGAAACTGCATCCATGGCAGCCGGCAGT 3784 Cys24OPheGTGACCGGGAATATGACT G CAAGGACATGAGCGATGAAGTTG TGC-TTCGCTGCGTTAATGGTGAGCGCTGGCCATCTGGTTTTCCGGAAAACCAGATGGCCAGCGCTCACCATTAACGCAGCCAACT 3785 TCATCGCTCATGTCCTTG CAGTCATATTCCCGGTCACACTGC CGGCTGCCATGGATGCAGTTTCCATCAGAGCACTGGA ATATGACT GCAAGGACA 3786 TGTCCTT G CAGTCATAT 3787 HypercholesterolaemiaAAACTGCATCCATGGCAGCCGGCAGTGTGACCGGGAATATG 3788 Asp245GluACTGCAAGGACATGAGCGA T GAAGTTGGCTGCGTTAATGGTG GATg-GAAAGCGCTGGCCATCTGGTTTTCCATCCCCCATTCTCTGTACAGAGAATGGGGGATGGAAAACCAGATGGCCAGCGCTCAC 3789 CATTAACGCAGCCAACTTC ATCGCTCATGTCCTTGCAGTCATA TTCCCGGTCACACTGCCGGCTGCCATGGATGCAGTTT ATGAGCGA TGAAGTTGG 3790 CCAACTTC A TCGCTCAT 3791 HypercholesterolaemiaATGGCAGCCGGCAGTGTGACCGGGAATATGACTGCAAGGAC 3792 Cys249TyrATGAGCGATGAAGTTGGCT G CGTTAATGGTGAGCGCTGGCC TGC-TACATCTGGTTTTCCATCCCCCATTCTCTGTGCCTTGCTGCTAGCAGCAAGGCACAGAGAATGGGGGATGGAAAACCAGATGG 3793 CCAGCGCTCACCATTAACG CAGCCAACTTCATCGCTCATGTC CTTGCAGTCATATTCCCGGTCACACTGCCGGCTGCCAT AGTTGGCT GCGUAATG 3794 CATTAACG C AGCCAACT 3795 HypercholesterolaemiaAGGCTCAGACACACCTGACCTTCCTCCTTCCTCTCTCTGGCT 3796 Glu256LysCTCACAGTGACACTCTGC G AGGGACCCAACAAGTTCAAGTGT cGAG-AAGCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCATGCAGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACACT 3797 TGAACTTGTTGGGTCCCT CGCAGAGTGTCACTGTGAGAGCCA GAGAGAGGAAGGAGGAAGGTCAGGTGTGTCTGAGCCT CACTCTGC GAGGGACCC 3798 GGGTCCCT C GCAGAGTG 3799 HypercholesterolaemiaCCTCTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAA 3800 Ser265ArgCAAGTTCAAGTGTCACAG C GGCGAATGCATCACCCTGGACAA AGCg-AGAAGTCTGCAACATGGCTAGAGACTGCCGGGACTGGTCATGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTTTGTC 3801 CAGGGTGATGCATTCGCC GCTGTGACACTTGAACTTGTTGGG TCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGAGAGG TGTCACAG CGGCGAATG 3802 CATTCGCC G CTGTGACA 3803 HypercholesterolaemiaTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCAACAAG 3804 Glu267LysTTCAAGTGTCACAGCGGC G AATGCATCACCCTGGACAAAGTC cGAA-AAATGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATGCATCTGACCAGTCCCGGCAGTCTCTAGCCATGTTGCAGACTT 3805 TGTCCAGGGTGATGCATT CGCCGCTGTGACACTTGAACTTGT TGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGA ACAGCGGC GAATGCATC 3806 GATGCATT C GCCGCTGT 3807 HypercholesterolaemiaTCTCTGGCTCTCACAGTGACACTCTGCGAGGGACCCMCAAG 3808 Glu267TermTTCAAGTGTCACAGCGGC G AATGCATCACCCTGGACAAAGTC cGAA-TAATGCAACATGGCTAGAGACTGCCGGGACTGGTCAGATGCATCTGACCAGTGCCGGCAGTCTCTAGCCATGTTGCAGACTT 3809 TGTCCAGGGTGATGCATT CGCCGCTGTGACACTTGAACTTGT TGGGTCCCTCGCAGAGTGTCACTGTGAGAGCCAGAGA ACAGCGGC GAATGCATC 3810 GATGCATT C GCCGCTGT 3811 HypercholesterolaemiaACACTCTGCGAGGGACCCAACAAGTTCAAGTGTCACAGCGG 3812 Lys273GluCGAATGCATCACCCTGGAC A AAGTCTGCAACATGGCTAGAGA cAAA-GAACTGCCGGGACTGGTCAGATGAACCCATCAAAGAGTGCGCGCACTCTTTGATGGGTTCATCTGACCAGTCCCGGCAGTCTC 3813 TAGCCATGTTGCAGACTT TGTCCAGGGTGATGCATTCGCCGC TGTGACACTTGAACTTGTTGGGTGCGTCGCAGAGTGT CCCTGGAC AAAGTCTGC 3814 GCAGACTT T GTCCAGGG 3815 HypercholesterolaemiaCGAGGGACCCAACAAGTTCAAGTGTCACAGCGGCGAATGCA 3816 Cys275TermTCACCCTGGACAAAGTCTG C AACATGGCTAGAGACTGCCGG TGCa-TGAGACTGGTCAGATGAACCCATCAAAGAGTGCGGTGAGTCTAGACTCACCGCACTCTTTGATGGGTTCATCTGACCAGTCCCG 3817 GCAGTCTCTAGCCATGTT GCAGACTTTGTCCAGGGTGATGCA TTCGCCGCTGTGACACTTGAACTTGTTGGGTCCCTCG AAAGTCTG CAACATGGC 3818 GCCATGTT G CAGACTTT 3819 HypercholesterolaemiaAGTTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAG 3820 Asp280GlyTCTGCPACATGGCTAGAG A CTGCCGGGACTGGTCAGATGAA GAC-GGCCCCATCAAAGAGTGCGGTGAGTCTCGGTCCAGGCGGCTAGCCGCCTGCACCGAGACTCACCGCACTCTTTGATGGGTTCA 3821 TCTGACCAGTCCCGGCAG TCTCTAGCCATGTTGCAGACTTTG TCCAGGGTGATGCATTCGCCGCTGTGACACTTGAACT GGCTAGAG ACTGCCGGG 3822 CCCGGCAG T CTCTAGCC 3823 HypercholesterolaemiaTCAAGTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCT 3824 Cys281TyrGCAACATGGCTAGAGACT G CCGGGACTGGTCAGATGAACCC TGC-TACATCAAAGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGATGGG 3825 TTCATCTGACCAGTCCCGG CAGTCTCTAGCCATGTTGCAGAC TTTGTCCAGGGTGATGCATTCGCCGCTGTGACACTTGA TAGAGACT GCCGGGACT 3826 AGTCCCGG C AGTCTCTA 3827 HypercholesterolaemiaTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAAC 3828 Asp283AsnATGGCTAGAGACTGCCGG G ACTGGTCAGATGAACCCATCAAA gGAC-AACGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGA 3829 TGGGTTCATCTGACCAG TCCCGGCAGTCTCTAGCCATGTTGC AGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACA ACTGCCGGG ACTGGTCA 3830 TGACCAGT C CCGGCAGT 3831 HypercholesterolaemiaTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACAT 3832 Asp283GluGGCTAGAGACTGCCGGGA C TGGTCAGATGAACCCATCAAAG GACt-GAGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTAAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTT 3833 GATGGGTTCATCTGACCA GTCCCGGCAGTCTCTAGCCATGTT GCAGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGA TGCCGGGA CTGGTCAGA 3834 TCTGACCA G TCCCGGCA 3835 HypercholesterolaemiaTGTCACAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAAC 3836 Asp283TyrATGGCTAGAGACTGCCGG G ACTGGTCAGATGAACCCATCAAA gGAC-TACGAGTGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACTCTTTGA 3837 TGGGTTCATCTGACCAGT CCCGGCAGTCTCTAGCCATGTTGC AGACTTTGTCCAGGGTGATGCATTCGCCGCTGTGACA ACTGCCGG GACTGGTCA 3838 TGACCAGT C CCGGCAGT 3839 HypercholesterolaemiaCAGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACATGG 3840 Trp284TermCTAGAGACTGCCGGGACTGG T CAGATGAACCCATCAAAGAGT TGGt-TGAGCGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTGTGCACAAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCACT 3841 CTTTGATGGGTTCATCTGA CCAGTCCCGGCAGTCTCTAGCCA TGTTGCAGACTTTGTCCAGGGTGATGCATTCGCCGCTG CGGGACTG GTCAGATGA 3842 TCATGTGA C CAGTCCCG 3843 HypercholesterolaemiaGCGGCGAATGCATCACCCTGGACAAAGTCTGCAACATGGCTA 3844 Ser285LeuGAGACTGCCGGGACTGGT C AGATGAACCCATCAAAGAGTGC TCA-TTAGGTGAGTCTCGGTGCAGGCGGCTTGCAGAGTTTGTGGGCCCACAAACTCTGCAAGCCGCCTGCACCGAGACTCACCGCA 3845 CTCTTTGATGGGTTCATCT GACCAGTCCCGGCAGTCTCTAGC CATGTTGCAGACTTTGTCCAGGGTGATGCATTCGCCGC GGACTGGT CAGATGAAC 3846 GTTCATCT G ACCAGTCC 3847 HypercholesterolaemiaCCCTGGACAAAGTCTGCAACATGGCTAGAGACTGCCGGGAC 3848 Lys290ArgTGGTCAGATGAACCCATCA A AGAGTGCGGTGAGTCTCGGTG " AAA-AGACAGGCGGCTTGCAGAGTTTGTGGGGAGCCAGGAAAGGGATCCCTTTCCTGGCTCCCCACAAACTCTGCAAGCCGCCTGCAC 3849 CGAGACTCACCGCACTCT TTGATGGGTTCATCTGACCAGTCC CGGCAGTCTCTAGCCATGTTGCAGACTTTGTCCAGGG ACCCATCA AAGAGTGCG 3850 CGCACTCT T TGATGGGT 3851 HypercholesterolaemiaGGGTAGGGGCCCGAGAGTGACCAGTCTGCATCCCCTGGCCC 3852 Cys297PheTGCGCAGGGACCAACGAAT G CTTGGACAACAACGGCGGCTG TGC-TTCTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTGCACTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACAG 3853 CCGCCGTTGTTGTCCAAG CATTCGTTGGTCCCTGCGCAGGG CCAGGGGATGCAGACTGGTCACTCTCGGGCCCCTACCC CAACGAAT GCTTGGACA 3854 TGTCCAAG C ATTCGTTG 3855 HypercholesterolaemiaGGGTAGGGGCCCGAGAGTGACCAGTCTGCATCCCCTGGCCC 3856 Cys297TyrTGCGCAGGGACCAACGAAT G CTTGGACAACAACGGCGGCTG TGC-TACTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTGCACTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACAG 3557 CCGCCGTTGTTGTCCAAG CATTCGTTGGTCCCTGCGCAGGG CCAGGGGATGCAGACTGGTCACTCTCGGGCCCCTACCC CAACGAAT GCTTGGACA 3858 TGTCCAAG C ATTCGTTG 3859 HypercholesterolaemiaTGCATCCCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGA 3860 His306TyrCAACAACGGCGGCTGTTCC C ACGTCTGCAATGACCTTAAGAT cCAC-TACCGGCTACGAGTGCCTGTGCCCCGACGGCTTGCAGCTGGCCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTAGCCGATC 3861 TTAAGGTCATTGCAGACGT GGGAACAGCCGCCGTTGTTGTCC AAGCATTCGTTGGTCCCTGCGCAGGGCCAGGGGATGCA GCTGTTCC CACGTCTGC 3862 GCAGACGT G GGAACAGC 3863 HypercholesterolaemiaCCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGACAACAA 3864 Cys308GlyCGGCGGCTGTTCCCACGTC T GCAATGACCTTAAGATCGGCTA cTGC-GGCCGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCGGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA 3865 GCCGATCTTAAGGTCATTG CAGACGTGGGAACAGCCGCCGT TGTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGGCCAGGG CCCACGTCT GCAATGAC 3866 GTCATTGC A GACGTGGG 3867 HypercholesterolaemiaCCTGGCCCTGCGCAGGGACCAACGAATGCTTGGACAACAAC 3868 Cys308TyrGGCGGCTGTTCCCACGTCT G CAATGACCTTAAGATCGGCTAC TGC-TACGAGTGCCTGTGCCCCGACGGCTTCCAGCTGGTGGCCCATGGGCCACCAGCTGGAAGCCGTCGGGGCACAGGCACTCGTA 3869 GCCGATCTTAAGGTCATTGBCAGACGTGGGAACAGCCGCCGTT GTTGTCCAAGCATTCGTTGGTCCCTGCGCAGGGCCAGG CCACGTCTG CAATGACC 3570 GGTCATTG C AGACGTGG 3871 HypercholesterolaemiaACCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTC 3872 Gly314SerTGCAATGACCTTAAGATC G GCTACGAGTGCCTGTGCCCCGAC cGGC-AGCGGCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCCGTCG 3873 GGGCACAGGCACTCGTAGC CGATCTTAAGGTCATTGCAGAC GTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCGTTGGT TTAAGATCGG CTACGAG 3874 CTCGTAGC C GATCTTAA 3875 HypercholesterolaemiaCCAACGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCT 3876 Gly314ValGCAATGACCTTAAGATCG G CTACGAGTGCCTGTGCCCCGAC GGC-GTCGGCTTCCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGATCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCCGTC 3877 GGGGCACAGGCACTCGTAG CCGATCTTAAGGTCATTGCAGA CGTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCGTTGG TAAGATCG GCTACGAGT 3878 ACTCGTAG C CGATCTTA 3879 HypercholesterolaemiaCGAATGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAA 3880 Tyr315TermTGACCTTAAGATCGGCTA C GAGTGCCTGTGCCCCGACGGCTT TACg-TAACCAGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCGAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGGAAGCC 3881 GTCGGGGCACAGGCACTC GTAGCCGATCTTAAGGTCATTGCA GACGTGGGAACAGCCGCCGTTGTTGTCCAAGCATTCG ATCGGCTA CGAGTGCCT 3882 AGGCACTC G TAGCCGAT 3883 HypercholesterolaemiaTGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAATGAC 3884 Cys317GlyCTTAAGATCGGCTACGAG T GCCTGTGCCCCGACGGCTTCCA gTGC-GGCGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCGGGCCCGGAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGG 3885 AAGCCGTCGGGGCACAGGCA CTCGTAGCCGATCTTAAGGTC ATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCCAAGCA GCTACGAG TGCCTGTGC 3886 GCACAGGC A CTCGTAGC 3887 HypercholesterolaemiaTGCTTGGACAACAACGGCGGCTGTTCCCACGTCTGCAATGAC 3888 Cys317SerCTTAAGATCGGCTACGAG T GCCTGTGCCCCGACGGCTTCCA gTGC-AGCGCTGGTGGCCCAGCGAAGATGCGAAGGTGATTTCCGGGCCCGGAAATCACCTTCGCATCTTCGCTGGGCCACCAGCTGG 3889 AAGCCGTCGGGGCACAGGC ACTCGTAGCCGATCTTAAGGTC ATTGCAGACGTGGGAACAGCCGCCGTTGTTGTCCAAGCA GCTACGAG TGCCTGTGC 3890 GCACAGGC A CTCGTAGC 3891 HypercholesterolaemiaACAACGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCG 3892 Pro320ArgGCTACGAGTGCCTGTGCC C CGACGGCTTCCAGCTGGTGGCC CCC-CGCCAGCGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTGGGCC 3893 ACCAGCTGGAAGCCGTCG GGGCACAGGCACTCGTAGCCGAT CTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTTGT CCTGTGCC CCGACGGCT 3894 AGCCGTCG G GGCACAGG 3895 HypercholesterolaemiaAACGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGC 3896 Asp321AsnTACGAGTGCCTGTGCCCC G ACGGCTTCCAGCTGGTGGCCCA cGAC-AACGCGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCCGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTGGG 3897 CCACCAGCTGGAAGCCGT CGGGGCACAGGCACTCGTAGCCG ATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCCGTT TGTGCCCC GACGGCTTC 3898 GAAGCCGT C GGGGCACA 3899 HypercholesterolaemiaCGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTA 3900 Asp321GluCGAGTGCCTGTGCCCCGA C GGCTTCCAGCTGGTGGCCCAGC GACg-GAGGAAGATGCGAAGGTGATTTCCGGGTGGGACTGAGCCCTAGGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCTG 3901 GGCCACCAGCTGGAAGCC GTCGGGGCACAGGCACTCGTAG CCGATCTRAGGTCATTGCAGACGTGGGAACAGCCGCCG TGCCCCGA CGGCTTGCA 3902 TGGAAGCC G TCGGGGCA 3903 HypercholesterolaemiaGGCGGCTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTAC 3904 Gly322SerGAGTGCCTGTGCCCCGAC G GCTTGCAGCTGGTGGCCCAGCG cGGC-AGCAAGATGCGAAGGTGATTTCCGGGTGGGAGTGAGCCCTGCAGGGCTCAGTCCCACCCGGAAATCACCTTCGCATCTTCGCT 3905 GGGCCACCAGCTGGAAGC CGTCGGGGCACAGGCACTCGTA GCCGATCTTAAGGTCATTGCAGACGTGGGAACAGCCGCC GCCCCGAC GGCTTCCAG 3906 CTGGAAGC C GTCGGGGC 3907 HypercholesteroiaemiaTGTTCCCACGTCTGCAATGACCTTAAGATCGGCTACGAGTGC 3908 Gln324TermCTGTGCCCCGACGGCTTC C AGCTGGTGGCCCAGCGAAGATG cCAG-TAGCGAAGGTGATTTCCGGGTGGGACTGAGCCCTGGGCCCCGGGGCCCAGGGCTCAGTCCCACCCGGAAATCACCTTCGCAT 3909 CTTCGCTGGGCCACCAGCT GGAAGCCGTCGGGGCACAGGCA CTCGTAGCCGATCTTAAGGTCATTGCAGACGTGGGAACA ACGGCTTC CAGCTGGTG 3910 CACCAGCT G GAAGCCGT 3911 HypercholesterolaemiaATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGGC 3912 Arg329ProTTCCAGCTGGTGGCCCAGC G AAGATGCGAAGGTGATTTCCG CGA-CCAGGTGGGACTGAGCCCTGGGCCCCCTCTGCGCTTCCTGACGTCAGGAAGCGCAGAGGGGGCCCAGGGCTCAGTCCCACCC 3913 GGAAATCACCTTCGCATCTT CGCTGGGCCACCAGCTGGAAG CCGTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCAT GGCCCAG CGAAGATGCG 3914 CGCATCTT C GCTGGGCC 3915 HypercholesterolaemiaAATGACCTTAAGATCGGCTACGAGTGCCTGTGCCCCGACGG 3916 Arg329TermCTTCCAGCTGGTGGCCCAG C GAAGATGCGAAGGTGATTTCC gCGA-TGAGGGTGGGACTGAGCCCTGGGCCCCCTCTGCGCTTCCTGATCAGGAAGCGCAGAGGGGGCCCAGGGCTCAGTCCCACCCG 3917 GAAATCACCTTCGCATCTTC GCTGGGCCACCAGCTGGAAGCC GTCGGGGCACAGGCACTCGTAGCCGATCTTAAGGTCATT TGGCCCAG CGAAGATGC 3918 GCATCTTC G CTGGGCCA 3919 HypercholesterolaemiaTCTAGCCATTGGGGAAGAGCCTCCCCACCAAGCCTCTTTCTC 3920 Glu336LysTCTCTTCCAGATATCGAT G AGTGTCAGGATCCCGACACCTGC tGAG-AAGAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGTACTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGGCTGCAG 3921 GTGTCGGGATCCTGACACT CATCGATATCTGGAAGAGAGAGA AAGAGGCTTGGTGGGGAGGCTCTTCCCCAATGGCTAGA ATATCGAT GAGTGTCAG 3922 CTGACAGT C ATCGATAT 3923 HypercholesterolaemiaCATTGGGGAAGAGCCTCCCCACCAAGCCTCTTTCTCTCTCTT 3924 Gln338TermCCAGATATCGATGAGTGT C AGGATCCCGAGACCTGCAGCCAG tCAG-TAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGTGCCAGTACTGGCACTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGG 3925 CTGCAGGTGTCGGGATCCT GACACTCATCGATATCTGGAAGA GAGAGAAAGAGGCTTGGTGGGGAGGCTGTTCCCCAATG ATGAGTGT CAGGATCCC 3926 GGGATCCT G ACACTCAT 3927 HypercholesterolaemiaTCCCCACCAAGCCTCTTTCTCTCTCTTCCAGATATCGATGAGT 3928 Cys343ArgGTCAGGATCCCGACACC T GCAGCCAGCTCTGCGTGAACCTG cTGC-CGCGAGGGTGGCTACAAGTGCCAGTGTGAGGAAGGCTTCCGGAAGCCTTCCTCACACTGGCACTTGTAGCCACCCTCCAGGT 3929 TCACGCAGAGCTGGCTGC AGGTGTCGGGATCCTGACACTCA TCGATATCTGGAAGAGAGAGAAAGAGGCTTGGTGGGGA CCGACACC TGCAGCCAG 3930 CTGGCTGC A GGTGTCGG 3931 HypercholesterolaemiaCAAGCCTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGA 3932 Gln345ArgTCCCGACACCTGCAGCC A GCTCTGCGTGAACCTGGAGGGTG CAG-CGGGCTACAAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGATCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTAGCCACCC 3933 TCCAGGTTCACGCAGAGC TGGCTGCAGGTGTCGGGATCCTG ACAGTCATCGATATCTGGAAGAGAGAGAAAGAGGCTTG CTGCAGCC AGCTCTGCG 3934 CGCAGAGC T GGCTGCAG 3935 HypercholesterolaemiaTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGATCCCGA 3936 Cys347TyrCACCTGCAGCCAGCTCT G CGTGAACCTGGAGGGTGGCTACA TGC-TACAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCCATGGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTA 3937 GCCACCCTCCAGGTTCAC GCAGAGCTGGCTGCAGGTGTCGG GATCCTGACACTCATCGATATCTGGAAGAGAGAGAAAGA CCAGCTCTG CGTGAACC 3938 GGTTCACG C AGAGCTGG 3939 HypercholesterolaemiaCTCTTTCTCTCTCTTCCAGATATCGATGAGTGTCAGGATCCCG 3940 Cys347ArgACACCTGCAGCCAGCTC T GCGTGAACCTGGAGGGTGGCTAC cTGC-CGCAAGTGCCAGTGTGAGGAAGGCTTCCAGCTGGACCCCCGGGGGTCCAGCTGGAAGCCTTCCTCACACTGGCACTTGTAG 3941 CCACCCTCCAGGTFCACGCA GAGCTGGCTGCAGGTGTCGGG ATCCTGACACTCATCGATATCTGGAAGAGAGAGAAAGAG GCCAGCTC TGCGTGAAC 3942 GTTCACGC A GAGCTGGC 3943 HypercholesterolaemiaCAGATATCGATGAGTGTCAGGATCCCGACACCTGCAGCCAGC 3944 Gly352AspTCTGCGTGAACCTGGAGG G TGGCTACAAGTGCCAGTGTGAG GGT-GATGAAGGCTTCCAGCTGGACCCCCACACGAAGGCCTGCAATTGCAGGCCTTCGTGTGGGGGTCCAGCTGGAAGCCTTCCTC 3945 ACACTGGCACTTGTAGCCA CCCTCCAGGTTCACGCAGAGCTG GCTGCAGGTGTCGGGATCCTGACACTCATCGATATCTG CCTGGAGG GTGGCTACA 3946 TGTAGCCA C CCTCCAGG 3947 HypercholesterolaemiaTCGATGAGTGTCAGGATCCCGACACCTGCAGCCAGCTCTGC 3948 Tyr354CysGTGAACCTGGAGGGTGGCT A CAAGTGCCAGTGTGAGGAAGG TAC-TGCCTTCCAGCTGGACCCCGACACGAAGGCCTGCAAGGCTGTACAGCCTTGCAGGCCTTCGTGTGGGGGTCCAGCTGGAAGCC 3949 TTCCTCACACTGGCACTTG TAGCCACCCTCCAGGTTCACGCA GAGCTGGCTGCAGGTGTCGGGATCCTGACACTCATCGA GGGTGGCT ACAAGTGCC 3950 GGCACTTG T AGCCACCC 3951 HypercholesterolaemiaCAGGATCCCGACACCTGCAGCCAGCTCTGCGTGAACCTGGA 3952 Cys358ArgGGGTGGCTACAAGTGCCAGTG T GAGGAAGGCTTCCAGCTGG gTGT-CGTACCCCCACACGAAGGCCTGCAAGGCTGTGGGTGAGCACGCGTGCTCACCCACAGCCTTGCAGGCCTTCGTGTGGGGGTCC 3953 AGCTGGAAGCCTTCCTCAC ACTGGCACTTGTAGCCACCCTCC AGGTTCACGCAGAGCTGGCTGCAGGTGTCGGGATCCTG AGTGCCAG TGTGAGGAA 3954 TTCCTCAC A CTGGCACT 3955 HypercholesterolaemiaTGCAGCCAGCTCTGCGTGAACCTGGAGGGTGGCTACAAGTG 3956 Gln3G3TermCCAGTGTGAGGAAGGCTTC C AGCTGGACCCCCACACGAAGG cCAG-TAGCCTGCAAGGCTGTGGGTGAGCACGGGAAGGCGGCGGGTGCACCCGCCGCCTTCCCGTGCTCACCCACAGCCTTGCAGGCC 3957 TTCGTGTGGGGGTCCAGCT GGAAGCCTTCCTCACACTGGCA CTTGTAGCCACCCTCCAGGTTCACGCAGAGCTGGCTGCA AAGGCTTC CAGCTGGAC 3958 GTCCAGCT G GAAGCCTT 3959

EXAMPLE 22 UDP-Glucuronosyitransferase—UGT1

[0144] Mutations in the human UGT1 gene result in a range of diseasesyndromes, ranging from relatively common diseases such as Gilbert'ssyndrome, which effects up to 7% of the population, to rare disorderssuch as Crigler-Najar syndrome. Symptoms of these diseases are theresult of diminished bilirubin conjugation and typically present withjaundice or, when mild, as an incidental finding during routinglaboratory analysis. Severe cases of Crigler-Najjar syndrome are causedby an absence of UGT1 activity and the majority of these patents die inthe neonatal period. The only known treatment is liver transplant Theattached table discloses the correcting oligonucleotide base sequencesfor the UGT1 oligonucleotides of the invention. TABLE 29 UGT1 Mutationsand Genome-Correcting Oligos Clinical Phenotype & SEQ ID MutationCorrecting Oligos NO: Crigler-Najjar syndromeGCAGGAGCAAAGGCGCCATGGCTGTGGAGTCCCAGGGCGG 3960 2 ACGCCCACTTGTCCTGGGCC TGCTGCTGTGTGTGCTGGGCC Leu15Arg CAGTGGTGTCCCATGCTGGGAAGATACTGTTGATCCCAGTCTG-CGG ACTGGGATCAACAGTATCTTCCCAGCATGGGACACCACTGGG 3961CCCAGCACACACAGCAGC A GGCCCAGGACAAGTGGGCGTCCGCCCTGGGACTCCACAGCCATGGCGCCTTTGCTCCTGC CCTGGGCCTGCTGCTGT 3962ACAGCAGCAGGCCCAGG 3963 Crigler-Najjar syndromeGGGAAGATACTGTTGATCCCAGTGGATGGCAGCCACTGGCT 3964 1 GAGCATGCTTGGGGCCATC CAGCAGCTGCAGCAGAGGGGAC Gln49Term ATGAAATAGTTGTCCTAGCACCTGACGCCTCGTTGTACACAG-TAG TGTACAACGAGGCGTCAGGTGCTAGGACAACTATTTCATGTC 3965CCCTCTGCTGCAGCTGCT G GATGGCCCCAAGCATGCTCAGCCAGTGGCTGCCATCCACTGGGATCAACAGTATCTTCCC GGGCCATC C AGCAGCTG 3966 CAGCTGCTG GATGGCCC 3967 Crugker-Najjar syndromeCAGCAGAGGGGACTGAAATAGTTGTCCTAGCACCTGACGCC 3968 1 TCGTTGTACATCAGAGAC GGAGCATTTTACACCTTGAAGACGT Gly71Arg ACCCTGTGCCATTCCAAAGGGAGGATGTGAAAGAGTGGA-AGA ACTCTTTCACATCCTCCCTTTGGAATGGCACAGGGTACGTCTT 3969CAAGGTGTAAAATGCTC C GTCTCTGATGTACAACGAGGCGTCAGGTGCTAGGACAACTATTTCATGTCCCCTCTGCTG TCAGAGAC G GAGCATTT 3970 AAATGCTC CGTCTCTGA 3971 Gilbert syndromeGGGTGAAGAACATGCTCATTTGCCTTTTCACAGAACTTTCTGTG 3972 Pro229GlnCGACGTGGTTTATTCCC C GTATGCAACCCTTGCCTCAGAATT CCG-CAGCCTTCAGAGAGAGGTGACTGTCCAGGACCTATTGAGCTCAATAGGTCCTGGACAGTCACCTCTCTCTGAAGGAATTCT 3973 GAGGCAAGGGTTGCATAC GGGGAATAAACCACGTCGCACAG AAAGTTCTGTGAAAAGGCAATGAGCATGTTCTTCACCC TTATTCCC CGTATGCAA 3974 TTGCATAC G GGGAATAA 3975 Crigler-Najjar syndromeTGTGAAGGATTACCCTAGGCCCATCATGCCCAATATGGTTTTT 3976 1 GTTGGTGGAATCAACTG CCTTCACCAAAATCCACTATCCCAG Cys280Term GTGTGTATTGGAGTGGGACTTTTACATGCGTATATTTGC-TGA AATATACGCATGTTAAAAGTCCCACTCCAATACACACCTGGGAT 3977AGTGGATTTTGGTGAAG G CAGTTGATTCCACCAACAAAAACCATATTGGGCATGATGGGCCTAGGGTAATCCTTCACA ATCAACTG C CTTCACCA 3978 TGGTGAAG GCAGTTGAT 3979 Crigler-Najjar syndromeATCAAAGAATATGAGAAAAAATTAACTGAAATTTTTCTTCTGG 3980 1 CTCTAGGAATTTGAAG CCTACATTAATGCTTCTGGAGAACATG Ala292Val GAATTGTGGTTTTCTCTTTGGGATCAATGGTCTCGCC-GTC GAGACCATTGATCCCPAAGAGAAAACCACAATTCCATGTTCTC 3981CAGAAGCATTAATGTAG G CTTCAAATTCCTAGAGCCAGAAGAAAAATTTTCAGTTAATTTTTTCTCATATTCTTTGAT ATTTGAAG C CTACATTA 3982 TAATGTAG GCTTCAAAT 3983 Crigler-Najjar syndromeAGGAATTTGAAGCCTACATTAATGCTTCTGGAGAACATGGAAT 3984 1 TGTGGTTTTCTCTTTGG GATCAATGGTCTCAGAAATTCCAGAG Gly308Glu AAGAAAGCTATGGCAATTGCTGATGCTTTGGGCAAGGA-GAA TTGCCCAAAGCATCAGCAATTGCCATAGCTTTCTTCTCTGGAA 3985TTTCTGAGACCATTGAT C CCAAAGAGAAAACCACAATTCCATGTTCTCCAGPAGCATTAATGTAGGCTTCAAATTCCT CTCTTTGG G ATCAATGG 3986 CCATTGAT CCCAAAGAG 3987 Crigler-Najjar syndromeGTCTCAGAAATTCCAGAGAAGAATTTGCTATGGCAATTGCTGAT 3988 1 GCTTTGGGCAAAATCCCT CAGACAGTAAGAAGATTCTATACCA Gln331Term TGGCCTCATATCTATTTTCACAGGAGCGCTAATCCCCAG-TAG GGGATTAGCGCTCCTGTGIAAAATAGATATGAGGCCATGGTAT 3989AGAATCTTCTTACTGTCT G AGGGATTTTGCCCAAAGCATCAGCAATTGCCATAGCTTTCTTCTCTGGAATTTCTGAGAC AAATCCCT C AGACAGTA 3990 TACTGTCT GAGGGATTT 3991 Crigler-Najjar syndromeTCTAATCATATTATGTTCTTTCTTTACGTTCTGCTCTTTTGCC 3992 1 CCTCCCAGGTCCTGTG GCGGTACACTGGAACCCGACCATCG Trp335Term AATCTTGCGAACAACACGATACTTGTTAAGTGGCTATGG-TGA TAGCCACTTAACAAGTATCGTGTTGTTCGCAAGATTCGATGGT 3993CGGGTTCCAGTGTACCG C CACAGGACCTGGGAGGGGCAAAAAGAGCAGAACGTAAAGAAAGAACATAATATGATTAGA GTCCTGTG G CGGTACAC 3994 GTGTACCGC CACAGGAC 3995 Crigler-Najjar syndromeACACTGGAACCCGACCATCGAATCTTGCGAACAACACGATAC 3996 1 TTGTTAAGTGGCTACCCC AAAACGATCTGCTTGGTATGTTGG Gln357Arg GCGGATTGGATGTATAGGTCAAACCAGGGTCTAAATTACAA-CGA TAATTTGACCCTGGTTTGACCTATACATCCAATCCGCCCAACA 3997TACCAAGCAGATCGTTT T GGGGTAGCCACTTAACAAGTATCGTGTTGTTCGCAAGATTCGATGGTCGGGTTCCAGTGT GCTACCCC A AAACGATC 3998 GATCGTTT TGGGGTAGC 3999 Crigler-Najjar syndromeTACACTGGAACCCGACCATCGAATCTTGCGAACAACACGATA 4000 1 CTTGTTAAGTGGCTACCC CAAAACGATCTGCTTGGTATGTTG Gln357Term GGCGGATTGGATGTATAGGTCAAACCAGGGTCAAATTCAA-TAA AATTTGACCCTGGTTTGACCTATACATCCAATCCGCCCAACAT 4001ACCAAGCAGATCGTTTT G GGGTAGCCACTTAACAAGTATCGTGTTGTTCGCAAGATTCGATGGTCGGGTTCCAGTGTA GGCTACCC C AAAACGAT 4002 ATCGTTTT GGGGTAGCC 4003 Gilbert syndromeAACTCAGAGATGTAACTGCTGACATCCTCCCTATTTTGCATCT 4004 Arg367GlyCAGGTCACCCGATGACC C GTGCCTTTATCACCCATGCTGGTT CGT-GGTCCCATGGTGTTTATGAAAGCATATGCAATGGCGTTCGAACGCCATTGCATATGCTTTCATAAACACCATGGGAACCAG 4005 CATGGGTGATAAAGGCAC GGGTCATCGGGTGACCTGAGATG CAAAATAGGGAGGATGTCAGCAGTTACATCTCTGAGTT CGATGACC CGTGCCTTT 4006 AAAGGCAC G GGTCATCG 4007 Crigler-Najjar syndromeTCAGAGATGTAACTGCTGACATCCTCCCTATTTTGCATCTCAG 4008 1 GTCACCCGATGACCCGT GCCTTTATCACCCATGCTGGTTCCC Ala368Thr ATGGTGTTTATGAAAGCATATGCAATGGCGTTCCCAGCC-ACC TGGGAACGCCATTGCATATGCTTTCATAAACACCATGGGAAC 4009CAGCATGGGTGATAAAGG C ACGGGTCATCGGGTGACCTGAGATGCAAAATAGGGAGGATGTCAGCAGTTACATCTCTGA TGACCCGT G CCTTTATC 4010 GATAAAGGC ACGGGTCA 4011 Crigler-Najjar syndromeCCTCCCTATTTTGCATCTCAGGTCACCCGATGACCCGTGCCT 4012 1 TTATCACCCATGCTGGTT CCCATGGTGTTTATGAAAGCATATG Ser375Phe CAATGGCGTTCCCATGGTGATGATGCCCTTGTTTGGTCC-TTC CCAAACAAGGGCATCATCACCATGGGAACGCCATTGCATATG 4013CTTTCATAAACACCATGG G AACCAGCATGGGTGATAAAGGCACGGGTCATCGGGTGACCTGAGATGCAAAATAGGGAGG TGCTGGTT C CCATGGTG 4014 CACCATGGG AACCAGCA 4015 Crigler-Najjar syndromeAGGTCACCCGATGACCCGTGCCTTTATCACCCATGCTGGTTC 4016 1 CCATGGTGTTTATGTAAAG CATATGCAATGGCGTTCCCATGGT Ser381Arg GATGATGCCCTTGTTTGGTGATCAGATGGACAATGCAAGC-AGG TGCATTGTCCATCTGATCACCAAACAAGGGCATCATCACCAT 4017GGGAACGCCATTGCATAT G CTTTCATAAACACCATGGGAACCAGCATGGGTGATAAAGGCACGGGTCATCGGGTGACCT TATGAAAG+E,UNE CATATGCAA 4018TTGCATAT G CTTTCATA 4019 Crigler-Najjar syndromeAGCATATGCAATGGCGTTCCCATGGTGATGATGCCCTTGTTT 4020 1 GGTGATCAGATGGACAAT GCAAAGCGCATGGAGACTAAGGG Ala401Pro AGCTGGAGTGACCCTGPATGTTCTGGAAATGACTTCTGGCA-CCA CAGAAGTCATTTCCAGAACATTCAGGGTCACTCCAGCTCCCT 4021TAGTCTCCATGCGCTTTG C ATTGTCCATCTGATCACCAAACAAGGGCATCATCACCATGGGAACGCCATTGCATATGCT TGGACAAT G CAAAGCGC 4022 GCGCTTTG CATTGTCCA 4023 Crigler Najjar syndromeGGAGCTGGAGTGACCCTGAATGTTCTGGAAATGACTTCTGAA 4024 1 GATTTAGAAAATGCTCTA AAAGCAGTCATCAATGACAAAAGGT Lys428Glu AAGAAAGAAGATACAGAAGAATACTTTGGTCATGGCAAA-GAA GCCATGACCAAAGTATTCTTCTGTATCTTCTTTCTTACCTTTTG 4025TCATTGATGACTGCTTTTAGAGCATT T TCTAAATCTTCAGAAGTCATTTCCAGAACATTCAGGGTCACTCCAGCTCC ATGCTCTA A AAGCAGTC 4026 GACTGCTT TTAGAGCAT 4027 Crigler-Najjar syndromeATGAGGCACAAGGGCGCGCCACACCTGCGCCCCGCAGGCCC 4028 1 ACGACCTCACCTGGTACCAG TACCATTCCTTGGACGTGATTG Tyr486Asp GTTTCCTCTTGGCGGTCGTGCTGACAGTGGCCTTCATCATAC-GAC TGATGAAGGCCACTGTCAGCACGACGGCCAAGAGGAAACCA 4029ATCACGTCCAAGGAATGGT A CTGGTACCAGGTGAGGTCGTGGGCTGCGGGGCGCAGGTGTGGCGCGCCCTTGTGCCTCAT GGTACCAG T ACCATTCC 4030GGAATGGT A CTGGTACC 4031 Crigler-Najjar syndromeACAAGGGCGCGCCACACCTGCGCCCCGCAGCCCACGACCT 4032 1 CACCTGGTACCAGTACCATT CCTTGGACGTGATTGGTTTCCT Ser488Phe CTTGGCCGTCGTGCTGACAGTGGCCTTCATCACCTTTAATCC-TTC TTAAAGGTGATGAAGGCCACTGTCAGCACGACGGCCAAGAG 4033GAAACCAATCACGTCCAAGGAATGGTACTGGTACCAGGTGAGGTCGTGGGCTGCGGGGCGCAGGTGTGGCGCGCCCTTGT GTACCATT C CTTGGACG 4034 CGTCCAAGG AATGGTAC 4035

EXAMPLE 23 Alzheimer's Disease—Amyloid Precursor Protein (APP)

[0145] Over the past few decades Alzheimer's disease (AD), onceconsidered a rare disorder, has become recognized as a major publichealth problem. Although there is no agreement on the exact prevalenceof Alzheimer's disease, in part due to difficulties of diagnosis,studies consistenty point to an exponential rise in prevalence of thisdisease with age. After age 65, the percentage of affected peopleapproximately doubles with every decade of life, regardless ofdefinition. Among people age 85 or older, studies suggest that 25 to 35percent have dementia, including Alzheimer's disease; one study reportsthat 47.2 percent of people over age 85 have Alzheimer's disease,exclusive of other dementias.

[0146] Alzheimer's disease progressively destroys memory, reason,judgment, language, and, eventually, the ability to carry out even thesimplest tasks. Anatomic changes associated with Alzheimer's diseasebegin in the entorhinal cortex, proceed to the hippocampus, and thengradually spread to other regions, particularly the cerebral cortex.Chief among such anatomic changes are the presence of characteristicextracellular plaques and internal neurofibrillary tangles.

[0147] At least four genes have been identified to date that contributeto development of Alzheimer's disease: AD1 is caused by mutations in theamyloid precursor gene (APP); AD2 is associated with a particular alleleof APOE (see Example 20); AD3 is caused by mutation in a gene encoding a7-transmembrane domain protein, presenilin-1 (PSEN1), and AD4 is causedby mutation in a gene that encodes a similar 7-transmembrane domainprotein, presenilin-2 (PSEN2). The attached table discloses thecorrecting oligonucleotide base sequences for the APP oligonucleotidesof the invention. TABLE 30 APP Mutations and Genome-Correcting OligosClinical Phenotype & SEQ ID Mutation Correcting Oligos NO: Alzheimerdisease CTGCATACTTTAATTATGATGTAATACAGGTTCTGGGTTGACA 4036 Glu665AspAATATCAAGACGGAGGA G ATCTCTGAAGTGAAGATGGATGCA GAG-GACGAATTCCGACATGACTCAGGATATGAAGTTCATCATATGATGAACTTCATATCCTGAGTCATGTCGGAATTCTGCATCC 4037 ATCTTCACTTCAGAGAT CTCCTCCGTCTTGATATTTGTCAACC CAGAACCTGTATTACATCATAATTAAAGTATGCAG ACGGAGGA GATCTCTGA 4038 TCAGAGAT C TCCTCCGT 4039 Alzheimer diseaseATTATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTT 4040 Ala692GlyCAAGGTGTTCTTTG C AGAAGATGTGGGTTCAAACAAAGGTGC GCA-GGAAATCATTGGACTCATGGTGGGCGGTGTTGTCATATGACAACACCGCCCACCATGAGTCCAATGATTGCACCTTTG 4041 TTTGAACCCACATCTTCT GCAAAGAACACCTTGAAAACAAATT AAGAAAAAGAATTTTAATTTCTAAATGCAATATAAT GTTCTTTG CAGAAGATG 4042 CATCTTCT G CAAAGAAC 4043 Alzheimer diseaseTATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTTC 4044 Glu693GlnAACGTGTTCTTTGCA G AAGATGTGGGTTCAAACAAAGGTGCA GAA-CAAATCATTGGACTCATGGTGGGCGGTGTTGTCATAGCTATGACAACACCGCCCACCATGAGTCCAATGATTGCACCTT 4045 TGTTTGAACCCACATCTT CTGCTAAAGAACACCTTGAAAACAAA TTAAGAAAAAGAATTTTAATTTCTAAATGCAATATA TCTTTGCAG AAGATGTG 4046 CACATCTT C TGCAAAGA 4047 Alzheimer diseaseATATTGCATTTAGAAATTAAAATTCTTTTTCTTAATTTGTTTTCA 4048 Glu693GlyAGGTGTTCTTTGCAG A AGATGTGGGTTCAAACAAAGGTGCAA GAA-GGATCATTGGACTCATGGTGGGCGGTGTTGTCATAGCGCTATGACAACACCGCCCACCATGAGTCCAATGATTGCACCT 4049 TTGTTTGAACCCACATCT TCTGCAAAGAACACCTTGAAAACAA ATTAAGAAAAAGAATTTTAATTTCTAAATGCAATAT CTTTGCAG AAGATGTGG 4050 CCACATCT T CTGCAA4G 4051 Alzheimer diseaseGAAGATGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATG 4052 Ala713ThrGTGGGCGGTGTTGTCATA G CGACAGTGATCGTCATCACCTTG GCG-ACGGTGATGCTGAAGAAGAAACAGTACACATCCATTCATCGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCACCAAGGT 4053 GATGACGATCACTGTCG CTATGACAACACCGCCCACCATGAG TCCAATGATTGCACCTTTGTTTGAACCCACATCTTC TTGTCATA GCGACAGTG 4054 CACTGTCG C TATGACAA 4055 SchizophreniaAAGATGTGGGTTCAAACAAAGGTGCAATCATTGGACTCATGG 4056 Ala713ValTGGGCGGTGTTGTCATAG C GACAGTGATCGTCATCACCTTGG GCG-GTGTGATGCTGAAGAAGAAACAGTACACATCCATTCATCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCACCAAGG 4057 TGATGACGATCACTGTC GCTATGACAACACCGCCCACCATGA GTCCAATGATTGCACCTTTGTTTGAACCCACATCTT TGTCATAG CGACAGTGA 4058 TCACTGTC G CTATGACA 4059 Alzheimer diseaseGTGGGTTCAAACTAAAGGTGCAATCATTGGACTCATGGTGGGC 4060 Val715MetGGTGTTGTCATAGCGACA G TGATCGTCATCACCTTGGTGATG GTG-ATGCTGAAGAAGTAAACAGTACACATCCATTCATCATGGTGCACCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCATCAC 4061 CAAGGTGATGACGATCA CTGTCGCTATGACAACACCGCCCAC CATGAGTCCAATGATTGCACCTTTGTTTGAACCCAC TAGCGACA GTGATCGTC 4062 GACGATCA C TGTCGCTA 4063 Alzheimer diseaseGGTTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGT 4064 Ile716ValGTTGTCATAGCGACAGTG A TCGTCATCACCTTGGTGATGCTG ATC-GTCAAGAAGAAACAGTACACATCCATTCATCATGGTGTGGCCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAGCAT 4065 CACCAAGGTGATGACGA TCACTGTCGCTATGACAACACCGCC CACCATGAGTCCAATGATTGCACCTTTGTTTGTAACC CGACAGTGA TCGTCATC 4066 GATGACGA T CACTGTCG 4067 Alzheimer diseaseCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTTG 4068 Val717GlyTCATAGCGACAGTGATCG T CATCACCTTGGTGATGCTGAAGA GTC-GGCAGAAACAGTACACATCCATTCATCATGGTGTGGTGGATCCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCA 4069 GCATCACCAAGGTGATG ACGATCACTGTCGCTATGACAACAC CGCCCACCATGAGTCCAATGATTGCACCTTTGTTTG AGTGATCG TCATCACCT 4070 AGGTGATG A CGATCACT 4071 Alzheimer diseaseTCAAACAAAGGTGCAATCATTGGACTCATGGTGGGCGGTGTT 4072 Val717IleGTCATAGCGACAGTGATC G TCATCACCTTGGTGATGCTGAAG GTC-ATCAAGAAACAGTACACATCCATTCATCATGGTGTGGTGGCCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAG 4073 CATCACCAAGGTGATGA CGATCACTGTCGCTATGACAACACC GCCCACCATGAGTCCAATGATTGCACCTTTGTTTGA CAGTGATC GTCATCACC 4074 GGTGATGA C GATCACTG 4075 Alzheimer diseaseTCAAACAAAGGTGCAATCATTCGACTCATGGTGGGCGGTGTT 4076 Val717PheGTCATAGCGACAGTGATC G TCATCACCTTGGTGATGCTGAAG GTC-TTCAAGAAACAGTACACATCCATTCATCATGGTGTGGTGGCCACCACACCATGATGAATGGATGTGTACTGTTTCTTCTTCAG 4077 CATCACCAAGGTGATGA CGATCACTGTCGCTATGACAACACC GCCCACGATGAGTCCAATGATTGCACCTTTGTTTGA CAGTGATC GTCATCACC 4078 GGTGATGA C GATCACTG 4079 Alzheimer diseaseTTGGACTCATGGTGGGCGGTGTTGTCATAGCGACAGTGATCG 4080 Leu723ProTCATCACCTTGGTGATGC T GAAGAAGAAACAGTACACATCCAT CTG-CCGTCATCATGGTGTGGTGGAGGTAGGTAAACTTGACTGCAGTCAAGTTTACCTACCTCCACCACACCATGATGAATGGAT 4081 GTGTACTGTTTCTTCTTC AGCATCACCAAGGTGATGACGATCA CTGTCGCTATGACAAGACCGCCCACCATGAGTCCAA GGTGATGC TGAAGAAGA 4082 TCTTCTTC A GCATCACC 4083

EXAMPLE 24 Alzheimer's Disease—Presenilin-1 (PSEN1)

[0148] The attached table discloses the correcting oligonucleotide basesequences for the PSEN1 oligonucleotides of the invention. TABLE 31PSEN1 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ IDMutation Correcting Oligos NO: Alzheimer diseaseCCCGGCAGGTGGTGGAGCAAGATGAGGAAGAAGATGAGGAG 4084 Ala79ValCTGACATTGAAATATGGCG C CAAGCATGTGATCATGCTCTTTG GCC-GTCTCCCTGTGACTCTCTGCATGGTGGTGGTCGTGGCTACGTAGCCACGACCACCACCATGCAGAGAGTCACAGGGACT 4085 GAGCATGATCACATGCTTG GCGCCATATTTCAATGTCAGCTC CTCATCTTCTTCCTCATCTTGCTCCACCACCTGCCGGG ATATGGCG CCAAGCATG 4086 CATGCTTG G CGCCATAT 4087 Alzheimer diseaseCAGGTGGAGCAAGATGAGGAAGAAGATGAGGAGCTGACATT 4068 Val82LeuGAAAATATGGCGCCAAGCAT G TGATCATGCTCTTTGTCCCTGT tGTG-CTGGACTCTCTGCATGGTGGTGGTCGTGGCTACCATTAAGTACTTAATGGTAGCCACGACCACCACCATGCAGAGAGTCACAG 4089 GGACAAAGAGCATGATCA CATGCTTGGCGCCATATTTCAATG TCAGCTCCTCATCTTCTTCCTCATCTTGCTCCACCAC CCAAGCAT GTGATCATG 4090 CATGATCA C ATGCTTGG 4091 Alzheimer diseaseAAATATGGCGCCAAGCATGTGATCATGCTCTTTGTCCCTGTG 4092 Val96PheACTCTCTGCATGGTGGTG G TCGTGGCTACCATTAAGTCAGTC gGTC-TTCAGCTTTTATACCCGGAAGGATGGGCAGCTGTACGTATATACGTACAGCTGCCCATCCTTCCGGGTATAAAAGCTGACTG 4093 ACTTAATGGTAGCCACGA CCACCACCATGCAGAGAGTCACAG GGACAAAGAGCATGATCACATGCTTGGCGCCATATTT TGGTGGTG GTCGTGGCT 4094 AGCCACGA C CACCACCA 4095 Alzheimer diseaseCTTTGTCCCTGTGACTCTCTGCATGGTGGTGGTCGTGGCTAC 4096 Phe105LeuCATTAAGTCAGTCAGCTT T TATACCCGGAAGGATGGGCAGCT TTTt-TTGGTACGTATGAGTTTTGTTTTATTATTCTCAAAGCCAGCTGGCTTTGAGAATAATAAAACAAAACTCATACGTACAGCTGC 4097 CCATCCTTCCGGGTATA AAAGCTGACTGACTTAATGGTAGCC ACGACCACCACCATGCAGAGAGTCACAGGGACAAAG GTCAGCTT TTATACCCG 4098 CGGTTATA A AAGCTGAC 4099 Alzheimer diseaseTGGTGATCTCCAITAACACTGACCTAGGGCTTFfGTGTTTGTT 4100 Thr116AsnTTATTGTAGAATCTATA C CCCATTCACAGAAGATACCGAGACT ACC-AACGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCGCATTCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCTCG 4101 GTATCTTCTGTGAATGGG GTATAGATTCTACAATAAAACAAAC ACAAAAGCCCTAGGTCAGTGTTAATGGAGATCACCA AATCTATA CCCCATTCA 4102 TGAATGGG G TATAGATT 4103 Alzheimer diseaseTGATCTCCATTAACACTGACCTAGGGCTTTGTGTTTGTTTTAT 4104 Pro117LeuTGTAGAATCTATACCC C ATTCACAGAAGATACCGAGACTGTG CCA-CTAGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTC 4105 TCGGTATCTTCTGTGAAT GGGGTATAGATTCTACAATAAAACA AACACAAAAGCCCTAGGTCAGTGTTAATGGAGATCA CTATACCC CATTCACAG 4106 CTGTGAAT G GGGTATAG 4107 Alzheimer diseaseTAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCT 4108 Glu120AspATACCCCATTCACAGA A GATACCGACACTGTGGGCCAGAGAG GAAg-GATCCCTGCACTCAATTCTGAATGCTGCCATCATGATCGAACAAGAAGGCAGCATCAGAATTGAGTGCAGGGCTCTCTG 4109 GCCCACAGTCTCGGTATC TTCTGTGAATGGGGTATAGATTCT ACAAATAAAACTAAACACAAAAGCCCTAGGTCAGTGTTA TTCACAGAA GATACCGA 4110 TCGGTATC T TCTGTGAA 4111 Alzheimer diseaseTAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCT 4112 Glu120AspATACCCCATTCACAGA A GATACCGAGACTGTGGGCCAGAGAG GAAg-GACCCCTGCACTCAATTCTGAATGCTGCCATCATGATCGATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTG 4113 GCCCACAGTCTCGGTATC TTCTGTGAATGGGGTATAGATTCT ACAATTAAAACAAACACAAAAGCCCTAGGTCAGTGTTA TTCACAGAA GATACCGA 4114 TCGGTATC T TCTGTGAA 4115 Alzheimer diseaseATTAACACTGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAAT 4116 Glu120LysCTATACCCCATTCACA G AAGATACCGAGACTGTGGGCCAGAG aGAA-AAAAGCCCTGCACTCAATTCTGAATGCTGCCATCATGATCATGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGC 4117 CCACAGTCTCGGTATCTT CTGTGAATGGGGTATAGATTCTACA ATAAAACAAACACAAAAGCCCTAGGTCAGTGTTAAT CATTCACA GAAGATACC 4118 GGTATCTT C TGTGAATG 4119 Alzheimer diseaseGACCTAGGGCTTTTGTGTTTGTTTTATTGTAGAATCTATACCC 4120 Glu123LysCATTCACAGAAGATACC G AGACTGTGGGCCAGAGAGCCCTG cGAG-AAGCACTCAATTCTGAATGCTGCCATCATGATCAGTGTCATGACACTGATCATGATGGCAGCATTCAGAATTGAGTGCAGGG 4121 CTCTCTGGCCCACAGTCT CGGTATCTTCTGTGAATGGGGTAT AGATTCTACAATAAAACAAACACAAAAGCCCTAGGTC AAGATACC GAGACTGTG 4122 CACAGTCT C GGTATCTT 4123 Aizheimer diseaseTATACCCCATTCACAGAAGATACCGAGACTGTGGGCCAGAGA 4124 Asn135AspGCCCTGCACTCAATTCTG A ATGCTGCCATCATGATCAGTGTC gAAT-GATATTGTTGTCATGACTATCCTCCTGGTGGTTCTGTATATATACAGAACCACCAGGAGGATAGTCATGACAACAATGACAC 4125 TGATCATGATGGCAGCAT TCAGAATTGAGTGCAGGGCTCTCT GCCCCACAGTCTCGGTATCTTCTGTGAATGGGGTATA CAATTCTG AATGCTGCC 4126 GGCAGCAT T CAGAATTG 4127 Alzheimer diseaseAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCAA 4128 Met139IleTTCTGAATGCTGCCATCAT G ATCAGTGTCATTGTTGTCATGAC ATGa-ATATATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTATATAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATG 4129 ACAACAATGACACTGAT CATGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCT GCCATCAT GATCAGTGT 4130 ACACTGAT C ATGATGGC 4131 Alzheimer diseaseCAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCA 4132 Met139LysATTCTGAATGCTGCCATCA T GATCAGTGTCATTGTTGTCATGA ATG-AAGCTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTATAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA 4133 CAACAATGACACTGATC ATGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTG TGCCATCA TGATCAGTG 4134 CACTGATC A TGATGGCA 4135 Alzheimer diseaseCAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTCA 4136 Met139ThrATTCTGAATGCTGCCATCA T GATCAGTGTCATTGTTGTCATGA ATG-ACGCTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTATAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA 4137 CAACAATGACACTGATC ATGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTG TGCCATCA TGATCAGTG 4138 CACTGATC A TGATGGCA 4139 Alzheimer diseaseACAGAAGATACCGAGACTGTGGGCCAGAGAGCCCTGCACTC 4140 Met139ValAATTCTGAATGCTGCCATCA T GATCAGTGTCATTGTTGTCATG cATG-GTGACTATCCTCCTGGTGGTTCTGTATAAATACAGGTGCTAGCACCTGTATTTATACAGAACCACCAGGAGGATAGTCATGA 4141 CAACAATGACACTGATCA TGATGGCAGCATTCAGAATTGAGT GCAGGGCTCTCTGGCCCACAGTCTCGGTATCTTCTGT CTGCCATC ATGATCAGT 4142 ACTGATCA T GATGGCAG 4143 Alzheimer diseaseGAGACTGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCT 4144 Ile143PheGCCATCATGATCAGTGTC A TTGTTGTCATGACTATCCTCCTGG cATT-TTTTGGTTCTGTATAAATACAGGTGCTATAAGGTGAGCATGCTCACCTTATAGCACCTGTATTTATACAGAACCACCAGGAG 4145 GATAGTCATGACAACAA TGACACTGATCATGATGGCAGCATTC AGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCTC TCAGTGTC ATTGTTGTC 4146 GACAACAA T GACACTGA 4147 Alzheimer diseaseAGACTGTGGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTG 4148 Ile143ThrCCATCATGATCAGTGTCA T TGTTGTCATGACTATCCTCCTGGT ATT-ACTGGTTCTGTATTAAATACAGGTGCTATAAGGTGAGCATATGCTCACCTTATAGCACCTGTATTTATACAGAACCACCAGGA 4149 GGATAGTCATGACAACA ATGACACTGATCATGATGGGAGCAT TCAGAATTGAGTGCAGGGCTCTCTGGCCCACAGTCT CAGTGTCA TTGTTGTCA 4150 TGACAACA A TGACACTG 4151 Alzheimer diseaseCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGAT 4252 Met146IleCAGTGTCATTGTTGTCAT G ACTATCCTCCTGG1GGTfCTGTAT ATGa-ATAAAATACAGGTGCTATAAGGTGAGCATGAGACACAGATCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGA 4153 ACCACCAGGAGGATAGTCAT GACAACAATGACACTGATCATG ATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGG GTTGTCAT GACTATCCT 4154 AGGATAGT C ATGACAAC 4155 Alzheimer diseaseCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGAT 4156 Met146IleCAGTGTCATTGTTGTCAT G ACTATCCTCCTGGTGGTTCTGTAT ATGa-ATCAAATACAGGTGCTATAAGGTGAGCATGAGACACAGATCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGA 4157 ACCAGCAGGAGGATAGT CATGACAACAATGACACTGATCATG ATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGG GTTGTCAT GACTATCCT 4158 AGGATAGT C ATGACAAC 4159 Alzheimer diseaseGGCCAGAGAGCCCTGCACTCTAATTCTGGAATGCTGCCATCATG 4160 Met146LeuATCAGTGTCATTGTTGTC A TGACTATCCTCCTGGTGGTTCTGT cATG-TTGATAAATACAGGTGCTATAAGGTGAGCATGAGACACATGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGAAC 4161 CACCAGGAGGATAGTCA TGACAACAATGACACTGATCATGAT GGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCC TTGTTGTC ATGACTATC 4162 GATAGTCA T GACAACAA 4163 Alzheimer diseaseGGCCAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATG 4164 Met146ValATCAGTGTCATTGTTGTC A TGACTATCCTCCTGGTGGTTCTGT CATG-GTGATAAATACAGGTGCTATAAGGTGAGCATGAGACACATGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACAGAAC 4165 CACCAGGAGGATAGTCA+E,UNTGACAACAATGACACTGATCATGAT GGCAGCATTCAGAATTGAGTGCAGGGCTCTCTGGCC TTGTTGTCA TGACTATC 4166 GATAGTCA T GACAACAA 4167 Alzheimer diseaseAGAGAGCCCTGCACTCAATTCTGAATGCTGCCATCATGATCA 4168 Thr147IleGTGTCATTGTTGTCATGA C TATCCTCCTGGTGGTTCTGTATAA ACT-ATTATACAGGTGCTATAAGGTGAGCATGAGACACAGATCGATCTGTGTCTCATGCTCACCTTATAGCACCTGTATTTATACA 4169 GAACCACCAGGAGGATA GTCATGACAACAATGACACTGATCA TGATGGCAGCATTCAGAATTGAGTGCAGGGCTCTCT TGTCATGA CTATCCTCC 4170 GGAGGATA G TCATGACA 4171 Alzheimer diseaseCTTTTTAAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTTT 4172 His163ArgCTTTTCTAGGTCATCC A TGCCTGGCTTATTATATCATCTCTATT CAT-CGTGTTGCTGTTCTTTITTrCATTCATTTACTTGGGCCCAAGTAAATGAATGAAAAATAGAACAGCAACAATAGAGATG 4173 ATATAATAAGCCAGGCA TGGATGACCTAGAAAAGAAAGCATTT CAATATAATTAACAGGTCCCACAACCCTTAAAAAG GGTCATCC ATGCCTGGC 4174 GCCAGGCA T GGATGACC 4175 Alzheimer diseaseACTTTTTAAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTT 4176 His163TyrTCTTTTCTAGGTCATC C ATGCCTGGCTTATTATATCATCTCTAT cCAT-TATTGTTGCTGTTCTTTTTTTCATTCATTTACTTGGCCAAGTAAATGAATGAAAAAAAGAACAGCAACAATAGAGATGA 4177 TATAATAAGCCAGGCAT GGATGACCTAGAAAAGAAAGCATTTC AATATAATTAACAGGTCCCACAACCCTTAAAAAGT AGGTCATC CATGCCTGG 4178 CCAGGCAT G GATGACCT 4179 Alzheimer diseaseAGGGTTGTGGGACCTGTTAATTATATTGAAATGCTTTCTTTTCT 4180 Trp165CysAGGTCATCCATGCCTG G CTTATTATATCATCTCTATTGTTGCT TGGc-TGCGTTCTTTTTTTCATTCATTTACTTGGGGTAAGTTAACTTACCCCAAGTAAATGAATGAAAAAAAGAACAGCAACAAT 4181 AGAGATGATATAATAAG CCAGGCATGGATGACCTAGAAAAGA AAGCATTTCAATATAATTAACAGGTCCCACAACCCT CATGCCTG GCTTATTAT 4182 ATAATAAG C CAGGCATG 4183 Alzheimer diseaseACGTGTTAATTATATTGAAATGCTTTCTTTTCTAGGTCATCCAT 4154 Ser169LeuGCCTGGCTTATTATAT C ATCTCTATTGTTGCTGTTCTTTTTTTC TCA-TTAATTCATTTACTTGGGGTAAGTTGTGAAATTTTTAAAAATTTCACAACTTACCCCAAGTAAATGAATGAAAAAAAGAA 4185 CAGCAACAATAGAGAT GATATAATAAGCCAGGCATGGATGAC CTAGAAAAGAAAGCATTTCAATATAATTAACAGGT TATTATAT CATCTCTAT 4186 ATAGAGAT G ATATAATA 4187 Alzheimer diseaseTAATTATATTGAAATGCTTTCTTTTCTAGGTCATCCATGCCTGG 4188 Leu171ProCTTATTATATCATCTC T ATTGTTGCTGTTCTTTTTTTCATTCATT GTA-CCATACTTGGGGTAAGTTGTGAAATTTTTGGTCTGCAGACCAAAAATTCACAACTTACCCCAAGTAAATGAATGAAA 4189 AAAAGAACAGCAACAAT AGAGATGATATAATAAGCCAGGCAT GGATGACCTAGAAAAGAAAGCATTTCAATATAATTA ATCATCTC TATTGTTGC 4190 GCAACAAT A GAGATGAT 4191 Alzheimer diseaseTATTGAAATGCTTTCTTTTCTAGGTCATCCATGCCTGGCTTATT 4192 Leu173TrpATATCATCTCTATTGT T GCTGTTCTTTTTTTCATTCATTTACTTG TTG-TGGGGGTAAGTTGTGAAATTTTTGGTCTGTCTTTCGAAAGACAGACCAAAAATTTCACAACTTACCCCAAGTAAATGA 4193 ATGAJAAAAAAGAACAGC AACAATAGAGATGATATAATAAGCCA GGCATGGATGACCTAGAAAAGAAAGCATTTCAATA TCTATTGT TGCTGTTCT 4194 AGAACAGC A ACAATAGA 4195 Alzheimer diseaseTATAACGTTGCTGTGGACTACATTACTGTTGCACTCCTGATCT 4196 Gly209ArgGGAATTTTGGTGTGGTG G GAATGATTTCCATTCACTGGTAAAG gGGA-AGAGTCCACTTCGACTCCAGCAGGCATATCTCATTATGATCATAATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTCC 4197 AGTGAATGGAAATCATTC CCACCACACCAAAATTCCAGATCAG GAGTGCAACAGTAATGTAGTCCACAGCAACGTTATA GTGTGGTG GGAATGATT 4198 AATCATTC C CACCACAC 4199 Alzheimer diseaseATAACGTTGCTGTGGACTACATTACTGTTGCACTCCTGATCTG 4200 Gly209ValGAATTTTGGTGTGGTGG G AATGATTTCCATTCACTGGAAAGGT GGA-GTACCACTTCGACTCCAGCAGGCATATCTCATTATGATATCATAATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTC 4201 CAGTGAATGGAAATCATT CCCACCACACCAAAATTCCAGATCA GGAGTGCAACAGTAATGTAGTCCACAGCAACGTTAT TGTGGTGG GAATGATTT 4202 AAATCATT C CCACCACA 4203 Alzheimer diseaseTGGACTACATTACTGTTGCACTCCTGATCTGGAATTTTGGTGT 4204 Ile213ThrGGTGGGAATGATTTCCA T TCACTGGAAAGGTCCACTTCGACT ATT-ACTCCAGCAGGCATATCTCATTATGATTAGTGCCCTCATATGAGGGCACTAATCATAATGAGATATGCCTGCTGGAGTCGA 4205 AGTGGACCTTTCCAGTGA ATGGAAATCATTCCCACCACACCA AAATTCCAGATCAGGAGTGCTAACAGTAATGTAGTCCA GATTTCCAT TCACTGGA 4206 TCCAGTGA A TGGAAATC 4207 Alzheimer diseaseCACTCCTGATCTGGAATTTTGGTGTGGTGGGAATGATTTCCAT 4208 Leu219ProTCACTGGAAAGGTCCAC T TCGACTCCAGCAGGCATATCTCAT CTT-CCTTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAATTGATAAACACCAGGGCCATGAGGGCACTAATCATAATGAGA 4209 TATGCCTGCTGGAGTCGA AGTGGACCTTTCCAGTGAATGGAA ATCATTCCCACCACACCAAAATTCCAGATCAGGAGTG AGGTCCAC TTCGACTCC 4210 GGAGTCGA A GTGGACCT 42TT Alzheimer diseaseATTTCCATTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCA 4212 Ala231ThrTATCTCATTATGATTAGT G CCCTCATGGCCCTGGTGTTTATCA tGCC-ACCAGTACCTCCCTGAATGGACTGCGTGGCTCATCTTGGCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGATAA 4213 ACACCAGGGCCATGAGGG CACTTAATCATAATGAGATATGCCT GCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAAAT TGATTAGTG CCCTCATG 4214 CATGAGGG C ACTAATCA 4215 Alzheimer diseaseTTTCCATTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCAT 4216 Ala231ValATCTCATTATGATTAGTG C CCTCATGGCCCTGGTGTTTATCAA GCC-GTCGTACCTCCCTGAATGGACTGCGTGGCTCATCTTGGCGCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTACTTGATA 4217 AACACCAGGGCCATGAGG GCACTAATCATAATGAGATATGCC TGCTGGAGTCGAAGTGGACCTTTCCAGTGAATGGAAA GATTAGTG CCCTCATGG 4218 CCATGAGG G CACTAATC 4219 Alzheimer diseaseTTCACTGGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCA 4220 Met233ThrTTATGATTAGTGCCCTCA T GGCCCTGGTGTTTATCAAGTACCT ATG-ACGCCCTGAATGGACTGCGTGGCTCATCTTGGCTGTGATATCACAGCCAAGATGAGCCACGCAGTCCATTCAGGGAGGTAC 4221 TTGATAAACACCAGGGCC ATGAGGGCACTAATCATAATGAGA TATGCCTGCTGGAGTCGAAGTGGACCTTTCCAGTGAA TGCCCTCA TGGCCCTGG 4222 CCAGGGCC A TGAGGGCA 4223 Alzheimer diseaseGGAAAGGTCCACTTCGACTCCAGCAGGCATATCTCATTATGA 4224 Leu235ProTTAGTGCCCTCATGGCCC T GGTGTTTATCAAGTACCTCCCTG GTG-CCGAATGGACTGCGTGGCTCATCTTGGCTGTGATTTCAGTACTGAAATCACAGCCAAGATGAGCCACGCAGTCCATTCAGGG 4225 AGGTACTTGATAAACACC AGGGCCATGAGGGCACTAATCATA ATGAGATATGCCTGCTGGAGTCGAAGTGGACCTTTCC CATGGCCC TGGTGTTTA 4226 TAAACACC A GGGCCATG 4227 Alzheimer diseaseTCATTATGATTAGTGCCCTCATGGCCCTGGTGTTTATCAAGTA 4228 Ala246GluCCTCCCTGAATGGACTG C GTGGCTCATCTTGGCTGTGATTTC GCG-GAGAGTATATGGTAAAACCCAAGACTGATAATTTGTTTGCAAACAAATTATCAGTCTTGGGTTTTACCATATACTGAAATCAC 4229 AGCCAAGATGAGCCAC GCAGTCCATTCAGGGAGGTACTTGAT AAACACCAGGGCCATGAGGGCACTAATCATAATGA ATGGACTG CGTGGCTCA 4230 TGAGCCAC G CAGTCCAT 4231 Alzheimer diseaseGTGCCCTCATGGCCCTGGTGTTTATCAAGTACCTCCCTGAAT 4232 Leu250SerGGACTGCGTGGCTCATCT TGGCTGTGATTTCAGTATATGGTA TTG-TCGAAACCCAAGACTGATAATTTGTTTGTCACAGGAATGCGCATTCCTGTGACTAAACAAATTATCAGTCTTGGGTTTTACCAT 4233 ATACTGAAATCACAGCC AAGATGAGCCACGCAGTCCATTCAG GGAGGTACTTGATAAACACCAGGGCCATGAGGGCAC GCTCATCT TGGCTGTGA 4234 TCACAGCC A AGATGAGC 4235 Alzheimer diseaseAGTTTAGCCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTT 4236 Ala260ValTTCTAGATTTAGTGG C TGTTTTGTGTCCGAAAGGTCCACTTCG GCT-GTTTATGCTGGTTGAAACAGCTCAGGAGAGTATGATCATTTCTCTCCTGAGCTGTTTCAACCAGCATACGAAGTGGAC 4237 CTTTCGGACACAAAACA GCCACTAATCTAGAAAAAGAAAAAC ATAAAAGACATCTAATAAAATGTATGGGCTAAACT TTTAGTGG CTGTTTTGT 4238 ACAAAACA G CCACTAAA 4239 Alzheimer diseaseCCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGA 4240 Leu262PheTTTAGTGGCTGTTTT G TGTCCGAAAGGTCCACTTCGTATGCTG TTGt-TTCGTTGAAACAGCTCAGGAGAGAAATGAAACGCTTAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCATACGA 4241 AGTGGACCTTTCGGACA CAAAACAGCCACTAAATCTAGAAAAA GAAAAACATAAAAGACATCTAATAAAATGTATGGG GCTGTTTT GTGTCCGAA 4242 TTCGGACA C AAAACAGC 4243 Alzheimer diseaseCCATACATTTTATTAGATGTCTTTTATGTTTTTCTTTTTCTAGAT 4244 Cys263ArgTTAGTGGCTGTTTG T GTCCGAAAGGTCCACTTCGTATGCTG gTGT-CGTGTTGAAACAGCTCAGGAGAGAAATGAAACGCTTTAAAGCGTTTCATTTCTCTCCTGAGCTGTTTCAACCAGCATACG 4245 AAGTGGACCTTTCGGAC ACAAAACAGCCACTAAATCTAGAAA AAGAAAAACATAAAAGACATCTAATAAAATGTATGG CTGTTTTG TGTCCGAAA 4246 TTTCGGAC A CAAAACAG 4247 Alzheimer diseaseACATTTTATTAGATGTCTTTATGTTTTTCTTTTTCTAGATTTAG 4248 Pro264LeuTGGCTGTTTTGTGTC C GAAAGGTCCACTTCGTATGCTGGTTG CCG-CTGAAACAGCTCAGGAGAGAAATGAAACGCTTTTTCCGGAAAAAGCGTTTCATTTCTCTCCTGAGCTGTTCAACCAGCA 4249 TACGAAGTGGACCTTTC GGACACAAAACAGCCACTAAATCTA GAAAAAGAAAAACATAAAAGACATCTAATAAAATGT TTTGTGTC CGAAAGGTC 4250 GACCTTTC G GACACAAA 4251 Alzheimer diseaseGTCTTTTATGTTTTTCTTTTTCTAGATTTAGTGGCTGTTTTGTG 4252 Arg269GlyTCCGAAAGGTCCACTT C GTATGCTGGTTGAAACAGCTCAGGA tCGT-GGTGAGAAATGAAACGCTTTTTCCAGCTCTCATTTACTAGTAAATGAGAGCTGGAAAAAGCGFTTCATTTCTCTCCTGAGC 4253 TGTTTCAACCAGCATAC GAAGTGGACCTTTCGGACACAAAAC AGCCACTAAATCTAGAAAAAGAAATACATAAAAGAC GTCCACTT CGTATGCTG 4254 CAGCATAC G AAGTGGAC 4255 Alzheimer diseaseTCTTTTATGTTTTTCTTTTTCTAGATTTAGTGGCTGTTTTGTGTC 4256 Arg269HisCGAAAGGTCCACTTC G TATGCTGGTTGAAACAGCTCAGGAGA CGT-CATGAAATGAAACGCTTTTTCCAGCTCTCATTTACTCGAGTTAAATGAGAGCTGGAAAAAGCGTTTCATTTCTCTCCTGAG 4257 CTGTTTCAACCAGCATA CGAAGTGGACCTTTCGGACACAAAA CAGCCACTAAATCTAGTAAAAAGAAAAACATAAAAGA TCCACTTCG TATGCTGG 4258 CCAGCATA C GAAGTGGA 4259 Alzheimer diseaseTAGTGGCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGG 4260 Arg278ThrTTGAAACAGCTCAGGAGA G AAATGAAACGCTTTTTCCAGCTCT AGA-ACACATTTACTCCTGTAAGTATTTGAGAATGATATTGAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAGAGCTG 4261 GAAAAAGCGTTTCATTT CTCTCCTGAGCTGTTTCAACCAGCAT ACGAAGTGGACCTTTCGGACACAAAACAGCCACTA TCAGGAGA GAAATGAAA 4262 TTTCATTT C TCTCCTGA 4263 Alzheimer diseaseCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAAC 4264 Glu280AlaAGCTCAGGAGAGAAATG A AACGCTTTTTCCAGCTCTCATTTAC GAA-GCATCCTGTAAGTATTTGAGAATGATATTGAATTAGTATACTAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAG 4265 AGCTGGAAAAAGCGTT TCATTTCTCTCCTGAGCTGTTTCAACC AGCATACGAAGTGGACCTTTCGGACACAAAACAG GAGAAATG AAACGCTTT 4266 AAAGCGTT T CATTTCTC 4267 Alzheimer diseaseCTGTTTTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAAC 4268 Glu280GlyAGCTCAGGAGAGAAATG A AACGCTTTTTCCAGCTCTCATTTAC GAA-GGATCCTGTAAGTATTTGAGAATGATATTGAATTAGTATACTAATTCAATATCATTCTCAAATACTTACAGGAGTAAATGAG 4269 AGCTGGAAAAAGCGTT TCATTTCTCTCCTGAGCTGTTTCAACC AGCATACGAAGTGGACCTTTCGGACACAAAACAG GAGAAATG AAACGCTTT 4270 AAAGCGTT T CATTTCTC 4271 Alzheimer diseaseTGTGTCCGAAAGGTCCACTTCGTATGCTGGTTGAAACAGCTC 4272 Leu282ArgAGGAGAGAAATGAAACGC T TTTTCCAGCTCTCATTTACTCCTG CTT-CGTTAAGTATTTGAGAATGATATTGAATTAGTAATCAGTACTGATTACTAATTCAATATCATTCTCAAATACTTACAGGAGTATTT AATGAGAGCTGGAAAA AGCGTTTCATTTCTCTCCTGAGCTGTT TCAACCAGCATACGAAGTGGACCTTTCGGACACA TGAAACGC TTTTTCCAG 4274 CTGGAAAA A GCGTTTCA 4275 Alzheimer diseaseAAGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGAGAA 4276 Ala285ValATGAAACGCTTTTTCCAG C TCTCATTTACTCCTGTAAGTATG GCT-GTTAGAATGATATTGAATTAGTAATCAGTGTAGAATTTAAATTCTACACTGATTACTAATTCAATATCATTCTCAAATACTTA 4277 CAGGAGTAAATGAGA GCTGGAAAAAGCGTTTCATTTCTCTCCT GAGCTGTTTCAACCAGCATACGAAGTGGACCTT TTTTCCAG CTCTCATTT 4278 AAATGAGA G CTGGAAAA 4279 Alzheimer diseaseGGTCCACTTCGTATGCTGGTTGAAACAGCTCAGGAGAGAAAT 4280 Leu286ValGAAACGCTTTTTCCAGCT C TCATTTACTCCTGTAAGTATTTGA tCTC-GTCGAATGATATTGAATTAGTAATCAGTGTAGAATTTATATAAATTCTACACTGATTACTAATTCAATATCATTCTCAAATACT 4281 TACAGGAGTAAATGAGA GCTGGAAAAAGCGTTTCATTTCTCTC CTGAGCTGTTTCAACCAGCATACGAAGTGGACC TTCCAGCT CTCATTTAC 4282 GTAAAT G AGAGCTGGAA 4283 Alzheimer diseaseGTGACCAACTTTTTAATATTTGTAACCTTTCCTTTTTAGGGGGA 4284 Gly384AlaGTAAAACTTGGATTGG G AGATTTCATTTTCTACAGTGTTCTGG GGA-GCATTGGTTAAAGCCTCAGCAACAGCCAGTGGAGACTGCAGTCTCCACTGGCTGTTGCTGAGGCTTTACCAACCAGAACA 4285 CTGTAGAAAATGAAATCT CCCAATCCAAGTTTTACTCCCCCTA AAAAGGAAAGGTTACAAATATTAAAAAGTTGGTCAC TGGATTGG GAGATTTCA 4286 TGAAATCT C CCAATCCA 4287 Alzheimer diseaseTTTGTAACCTTTCCTTTTTAGGGGGAGTAAAACTTGGATTGGG 4288 Ser390IleAGATTTCATTTTCTACA G TGTTCTGGTTGGTAAAGCCTCAGCA AGT-ATTACAGCCAGTGGAGACTGGAACACAACCATAGCCTGCAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTGCTGAG 4289 GCTTTACCAACCAGAACA CTGTAGAAAATGAPTATCTCCCAATC CAAGTTTTACTCCCCCTAAAAAGGAAAGGTTACAAA TTTCTACAG TGTTCTGG 4290 CCAGAACA C TGTAGAAA 4291 Atzheimer diseaseAACCTTTCCTTTTTAGGGGGAGTAAAACTTGGATTGGGAGATT 4292 Leu392ValTCATTTTCTACAGTGTT C TGGTTGGTAAAGCCTCAGCAACAGC tCTG-GTGCAGTGGAGACTGGAACACAACCATAGCCTGTTTCGCGAAACAGGCTATGGTTGTGTTCCAGTCTCCACTGGCTGTTG 4293 CTGAGGCTTTACCAACCA GAACACTGTAGAAAATGAAATCTCC CAATCCAAGTTTTACTCCCCCTAAAAAGGAAAGGTT ACAGTGTT CTGGTTGGT 4294 ACCAACCA G AACACTGT 4295 Alzheimer diseaseATTTCATTTTCTACAGTGTTCTGGTTGGTAAAGCCTCAGCAAC 4296 Asn405SerAGCCAGTGGAGACTGGA A CACAACCATAGCCTGTTTCGTAGC AAGAGCCATATTAATTGTAAGTATACACTAATAAGAATGTGTACACATTCTTATTAGTGTATACTTACAATTAATATGGCTACGAA 4297 ACAGGCTATGGTTGTG TTCCAGTCTCCACTGGCTGTGCTGA GGCTTTACCAACCAGAACACTGTAGAAAATGAAAT AGACTGGA ACACAACCA 4298 TGGTTGTG T TCCAGTCT 4299 Alzheimer diseaseTACAGTGTTCTGGTTGGTAAAGCCTCAGCAACAGCCAGTGGA 4300 Ala409ThrGACTGGAACACAACCATA G CCTGTTTCGTAGCCATATTAATTG aGCC-ACCTAAGTATACACTAATAAGAATGTGTCAGAGCTCTTATAAGAGCTCTGACACATTCTTATTAGTGTATACTTACAATTAAT 4301 ATGGCTACGAAACAGG CTATGGTTGTGTTCCAGTCTCCACTG GCTGTTGCTGAGGCTTTACCAACCAGAACACTGTA CAACCATA GCCTGTTTC 4302 GAAACAGG C TATGGTTG 4303 Alzheimer diseaseGTGTTCTGGTTGGTAAAGCCTCAGCAACAGCCAGTGGAGACT 4304 Cys410TyrGGAACACAACCATAGCCT G TTTCGTAGCCATATTAATTGTAAG TGT-TATTATACACTAATAAGAATGTGTCAGAGCTCTTAATGTACATTAAGAGCTCTGACACATTCTTATTAGTGTATACTTACAAT 4305 TAATATGGCTACGAAA CAGGCTATGGTTGTGTTCCAGTCTCCA CTGGCTGTTGCTGAGGCTTTACCAACCAGAACAC CATAGCCT GTTTCGTAG 4306 CTACGAAA C AGGCTATG 4307 Alzheimer diseaseTGTGAATGTGTGTCTTTCCCATCTTCTCCACAGGGTTTGTGCC 4308 Ala426ProTTACATTATTACTCCTT G CCATTTTCAAGAAAGCATTGCCAGCT tGCC-CCCCTTCCAATCTCCATCACCTTTGGGCTTGTTTTCTAGAAAACAAGCCCAAAGGTGATGGAGATTGGAAGAGCTGGCA 4309 ATGCTTTCTTGAAAATGG CAAGGAGTAATAATGTAAGGCACAA ACCCTGTGGAGAAGATGGGAAAGACACACATTCACA TACTCCTT GCCATTTTC 4310 GAAAATGG C AAGGAGTA 43TT Alzheimer diseaseAGGGTTTGTGCCTTACATTATTACTCCTTGCCATTTTCAAGAA 4312 Pro436GlnAGCATTGCCAGCTCTTC C AATCTCCATCACCTTTGGGCTTGTT CCA-CAATTCTACTTTGCCACAGATTATCTTGTACAGCCTTTAAAGGCTGTACAAGATAATCTGTGGCAAAGTAGAAAACAAGC 4313 CCAAAGGTGATGGAGATT GGAAGAGCTGGCAATGCTTTCTTG AAAATGGCAAGGAGTAATAATGTAAGGCACAAACCCT AGCTCTTC CAATCTCCA 4314 TGGAGATT G GAAGAGCT 4315 Alzheimer diseaseCAGGGTTTGTGCCTTACATTATTACTCCTTGCCATTTTCAAGA 4316 Pro436SerAAGCATTGCCAGCTCTT C CAATCTCCATCACCTTtGGGCTTGT tCCA-TCATTTCTACTTTGCCACAGATTATCTTGTACAGCCTTAAGGCTGTACAAGATAATCTGTGGCAAAGTAGAAAACAAGCC 4317 CAAAGGTGATGGAGATTG GAAGAGCTGGCAATGCTTTCTTGA AAATGGCAAGGAGTAATAATGTAAGGCACAAACCCTG CAGCTCTT CCAATCTCC 4318 GGAGATTG G AAGAGCTG 4319

EXAMPLE 25 Alzheimere's Disease—Presenilin-2 (PSEN2)

[0149] The attached table discloses the correcting oligonucleotide basesequences for the PSEN2 oligonucleotides of the invention. TABLE 32PSEA2 Mutations and Genome-Correcting Oligos Clinical Phenotype & SEQ IDMutation Correcting Oligos NO: Alzheimer diseaseGATGTGGTTTCCCACAGAGAAGCCAGGAGAACGAGGAGGAC 4320 Arg62HisGGTGAGGAGGACCCTGACC G CTATGTCTGTAGTGGGGTTCC CGGCACCGGGCGGCCGCCAGGCCTGGAGGAAGAGCTGACCCTCAATTGAGGGTCAGCTCTTCCTCCAGGCCTGGCGGCCGCCCGGG 4321 AACCCCACTACAGACATAG CGGTCAGGGTCCTCCTCACCGTC CTCCTCGTTCTCCTGGCTTCTCTGTGGGAAACCACATC CCCTGACC GCTATGTCT 4322 AGACATAG C GGTCAGGG 4323 Alzheimer diseaseGCCTCGAGGAGCAGTCAGGGCCGGGAGCATCAGCCCTTTGC 4324 Thr122ProCTTCTCCCTCAGCATCTAC A CGACATTCACTGAGGACACACC cACG-CCGCTCGGTGGGCCAGCGCCTCCTCAACTCCGTGCTGAACATGTTCAGCACGGAGTTGAGGAGGCGCTGGCCCACCGAGGGT 4325 GTGTCCTCAGTGAATGTCG TGTAGATGCTGAGGGAGAAGGCA AAGGGCTGATGCTCCCGGCCCTGACTGCTCCTCGAGGC GCATCTAC ACGACATTC 4326 GAATGTCG T GTAGATGC 4327 Alzheimer diseaseACACGCCATTCACTGAGGACACACCCTCGGTGGGCCAGCGC 4328 Asn141IleCTCCTCAACTCCGTGCTGA A CACCCTCATCATGATCAGCGTC AAGATCATCGTGGTTATGACCATCTTCTTGGTGGTGCTCTACAATTGTAGAGCACCACCAAGAAGATGGTCATAACCACGATGACG 4329 CTGATCATGATGAGGGTG TTCAGCACGGAGTTGAGGAGGCG CTGGCCCACCGAGGGTGTGTCCTCAGTGAATGGCGTGT CGTGCTGA ACACCCTCA 4330 TGAGGGTG T TCAGCACG 4331 Alzheimer diseaseCCACTGGAAGGGCCCTCTGGTGCTGCAGCAGGCCTACCTCA 4332 Met239IleTCATGATCAGTGCGCTCAT G GCCCTAGTGTTCATCAAGTACCT ATGg-ATACCCAGAGTGGTCCGCGTGGGTCATCCTGGGCGCCATC Clinical Phenotype & SEQ IDMutation Correcting Oligos NO: GATGGCGCCCAGGATGACCCACGCGGACCACTCTGGGAGGT4333 ACTTGATGAACACTAGGGC C ATGAGCGCACTGATCATGATGAGGTAGGCCTGCTGCAGCACCAGAGGGCCCTTCCAGTGG GCGCTCAT G GCCCTAGT 4334 ACTAGGGCC ATGAGCGC 4335 Alzheimer diseaseATCCACTGGAAGGGCCCTCTGGTGCTGCAGCAGGCCTACCT 4336 Met239ValCATCATGATCAGTGCGCTC A TGGCCCTAGTGTTCATCAAGTA cATG-GTGCCTCCCAGAGTGGTCCGCGTGGGTCATCCTGGGCGCCATGGCGCCCAGGATGACCCACGCGGACCACTCTGGGAGGTAC 4337 TTGATGAACACTAGGGCCA TGAGCGCACTGATCATGATGAGG TAGGCCTGCTGCAGCACCAGAGGGCCCTTCCAGTGGAT GTGCGCTC ATGGCCCTA 4338 TAGGGCCA T GAGCGCAC 4339

EXAMPLE 26 Plant Cells

[0150] The oligonucleotides of the invention can also be used to repairor direct a mutagenic event in plants and animal cells. Although littleinformation is available on plant mutations amongst natural cultivars,the oligonucleotides of the invention can be used to produce “knock out”mutations by modification of specific amino acid codons to produce stopcodons (e.g., a CAA codon specifying Gln can be modified at a specificsite to TAA; a AAG codon specifying Lys can be modified to UAG at aspecific site; and a CGA codon for Arg can be modified to a UGA codon ata specific site). Such base pair changes will terminate the readingframe and produce a defective truncated protein, shortened at the siteof the stop codon. Alternatively, frameshift additions or deletions canbe directed into the genome at a specific sequence to interrupt thereading frame and produce a garbled downstream protein. Such stop orframeshift mutations can be introduced to determine the effect ofknocking out the protein in either plant or animal cells.

[0151] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. An oligonucleotide for targeted alteration(s) ofgenetic sequence, comprising a single-stranded oligonucleotide having aDNA domain, said DNA domain having at least one mismatch with respect tothe genetic sequence to be altered, and further comprising chemicalmodifications within the oligonucleotide, said targeted alteration(s)occurring more frequently than alteration(s) of the genetic sequence bya double-stranded double hairpin chimeric oligonucleotide containing RNAand DNA nucleotides.
 2. The oligonucleotide according to claim one thatcomprises at least one phosphorothioate linkage within theoligonucleotide.
 3. The oligonucleotide according to claim one thatcomprises a 2′-O-methyl analog.
 4. The oligonucleotide according toclaim one that comprises a locked nucleotide analog.
 5. Theoligonucleotide according to claim one that comprises a combination ofat least two modifications selected from the group of a phosphorothioatelinkage, a 2′-O-methyl analog, a locked nucleotide analog and aribonucleotide.
 6. The oligonucleotide according to any one of claims 1to 5 that comprises at least one unmodified ribonucleotide.
 7. Theoligonucleotide according to any one of claims 1 to 6, wherein thesequence of said oligonucleotide is selected from the group consistingof SEQ ID NOS: 1-4339.
 8. A method of targeted alteration of geneticmaterial, comprising combining the target genetic material with anoligonucleotide according to any one of claims 1 to 7 in the presence ofpurified proteins.
 9. A method of targeted alteration of geneticmaterial, comprising administering to a cell extract an oligonucleotideof any one of claims 1 to
 7. 10. A method of targeted alteration ofgenetic material, comprising administering to a cell an oligonucleotideof any one of claims 1 to
 7. 11. A method of targeted alteration ofgenetic sequence in a subject, comprising administering to the subjectan oligonucleotide of any one of claims 1 to
 7. 12. A method of targetedalteration of genetic sequence, comprising combining target geneticmaterial with an oligonucleotide according to any one of claims 1 to 7,said target genetic material being a non-transcribed DNA strand of aduplex DNA.
 13. The genetic material obtained by any one of the methodsof claim 8, 9 or claim
 10. 14. A cell comprising the genetic material ofclaim
 13. 15. A non-human organism comprising the cell according toclaim
 14. 16. A pharmaceutical composition comprising theoligonucleotide according to any one of claims 1 to
 7. 17. A method oftargeted chromosomal genomic alteration, comprising administering thepharmaceutical composition of claim 16 to a subject.
 18. A non-humanorganism produced by the method of claim 11 or claim
 17. 19. A method ofoptimizing an oligonucleotide for targeted alteration of a geneticsequence, which comprises: (a) comparing the efficiency of alteration ofa targeted genetic sequence by an oligonucleotide of any one of claims 1to 7 with the efficiency of alteration of the same targeted geneticsequence by a second oligonucleotide, said second oligonucleotideselected from the group of (1) an oligonucleotide that is fullycomplementary to the target and lacks the mismatch, (2) a fully modifiedphosphorothiolated oligonucleotide, (3) a fully modified 2′-O-methylatedoligonucleotide and (4) a chimeric double-stranded double hairpincontaining RNA and DNA nucleotides.
 20. The method of claim 19 in whichthe alteration is produced in a cell extract.
 21. The method of claim 20in which the cell extract is selected from the group of a fungal cellextract, a plant cell extract, a rodent cell extract, a primate cellextract and a human cell extract.
 22. The method of claim 19 in whichthe alteration is produced in a cell.
 23. The method of claim 21 inwhich the cell is selected from the group of a fungal cell, a plantcell, a rodent cell, a primate cell and a human cell.
 24. A kitcomprising the oligonucleotide according to any one of claims 1 to 7 anda second oligonucleotide selected from the group of (1) anoligonucleotide that is fully complementary to the target and lacks themismatch, (2) a fully modified phosphorothiolated oligonucleotide, (3) afully modified 2-O-methylated oligonucleotide and (4) a chimeric doublestranded double hairpin containing RNA and DNA nucleotides.